U.S. patent number 6,376,672 [Application Number 09/542,303] was granted by the patent office on 2002-04-23 for naphthalenylmethoxypiperidines as renin inhibitors.
This patent grant is currently assigned to Hoffmann-La Roche Inc.. Invention is credited to Volker Breu, Hans-Peter Marki, Eric Vieira, Wolfgang Wostl.
United States Patent |
6,376,672 |
Breu , et al. |
April 23, 2002 |
**Please see images for:
( Certificate of Correction ) ** |
Naphthalenylmethoxypiperidines as renin inhibitors
Abstract
The present invention relates to compound of formula (I)
##STR1## wherein R.sup.1, R.sup.2 and R.sup.3 are as defined in the
description and claims and pharmaceutically acceptable salts
thereof. The compounds are useful for treating diseases associated
with restenosis, glaucoma, cardiac infarct, high blood pressure and
end organ damage, e.g. cardiac insufficiency and kidney
insufficiency.
Inventors: |
Breu; Volker (Schliengen,
DE), Marki; Hans-Peter (Basel, CH), Vieira;
Eric (Allschwil, CH), Wostl; Wolfgang
(Grenzach-Wyhlen, DE) |
Assignee: |
Hoffmann-La Roche Inc. (Nutley,
NJ)
|
Family
ID: |
8238050 |
Appl.
No.: |
09/542,303 |
Filed: |
April 4, 2000 |
Foreign Application Priority Data
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Apr 27, 1999 [EP] |
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99108199 |
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Current U.S.
Class: |
546/205;
546/210 |
Current CPC
Class: |
A61P
9/04 (20180101); A61P 9/10 (20180101); A61P
13/12 (20180101); C07D 233/56 (20130101); A61P
43/00 (20180101); C07D 249/08 (20130101); A61P
27/06 (20180101); C07D 211/42 (20130101); A61P
13/00 (20180101); C07D 231/12 (20130101); A61P
9/12 (20180101); A61P 9/00 (20180101) |
Current International
Class: |
C07D
211/42 (20060101); C07D 211/00 (20060101); C07D
521/00 (20060101); C07D 211/42 (); A61K
031/445 () |
Field of
Search: |
;514/319,326
;546/205,210 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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0 273 199 |
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Jul 1988 |
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EP |
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273199 |
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Jul 1988 |
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EP |
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0 339 579 |
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Nov 1989 |
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EP |
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WO 97/09311 |
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Mar 1997 |
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WO |
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Other References
Robinson, P.L. et al., Phosphorus and Sulfur, 26, pp. 15-24 (1986).
.
Jaegeer E. and Biel, J.H., J. Org. Chem., 30 (3), pp 740-744
(1965). .
Mancuso A.J. and Swern D., Synthesis, p 165-185 (1981). .
Houben-Weyl, Organic Chemistry, vol. E21, p 81, (1991). .
Fischli W. et al., Hypertension, 18 (1), pp. 22-31 (1991). .
Clozel J.-P. et al, Hypertension, 22 (1), pp 9-17 (1993). .
Pals, D.T. et al., Hypertension, 8, pp 1105-1112 (1986). .
Dellaria J.F. et al., J. Med. Chem., 30, pp 2137-2144 (1987). .
Kokubu T. et al., Biochem. Biophys. Res. Commun., 118, pp 929-933
(1984). .
Boger J. et al., J. Med. Chem., 28, pp 1779-1790 (1985). .
Luft F.C. et al., Hypertension, 33, Part II, pp 212-218 (1999).
.
Mervaala E.M.A. et al, Hypertension, 33, Part II, pp 389-395
(1999). .
Vieira E. et al., Bioorganic & Medicinal Chemistry Letters, 9,
pp 1397-1402 (1999)..
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Primary Examiner: Chang; Ceila
Attorney, Agent or Firm: Johnston; George W. Parise; John
P.
Claims
What is claimed is:
1. A compound of the formula: ##STR12##
wherein
R.sup.1 is naphthyl or naphthyl substituted by one to three C.sub.1
-C.sub.5 -alkoxy groups;
R.sup.2 is phenyl; phenyl substituted by one to three substituents
independently selected from the group consisting of halogen, cyano,
C.sub.1 -C.sub.3 -alkoxy, and nitro; benzyl; or benzyl substituted
by one to three substituents independently selected from the group
consisting of halogen, cyano, C.sub.1 -C.sub.3 -alkoxy, and
nitro;
R.sup.3 is H--[CH(OR.sup.4)].sub.2 --CH.sub.2 --O--CH.sub.2 -- or
R.sup.3a --(CH.sub.2).sub.k --[CH(OR.sup.4)].sub.1 --CH.sub.2
--O--;
R.sup.3a is hydroxy or C.sub.1 -C.sub.3 -alkoxy;
R.sup.4 is hydrogen or C.sub.1 -C.sub.3 -alkyl;
k is 1 or 2;
l is 1 or 2; or
a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1, wherein R.sup.1 is
naphthyl.
3. The compound according to claim 1, wherein R.sup.1 is naphthyl
substituted by one to three C.sub.1 -C.sub.5 -alkoxy groups.
4. The compound according to claim 3, wherein R.sup.1 is naphthyl
substituted by one C.sub.1 -C.sub.3 -alkoxy group.
5. The compound according to claim 4, wherein R.sup.1 is naphthyl
substituted by methoxy.
6. The compound according to claim 5, wherein R.sup.1 is
4-methoxy-naphthalen-2yl.
7. The compound according to claim 1, wherein R.sup.2 is phenyl or
benzyl.
8. The compound according to claim 7, wherein R.sup.2 is
phenyl.
9. The compound according to claim 7, wherein R.sup.2 is
benzyl.
10. The compound according to claim 1, wherein R.sup.2 is phenyl
substituted by one to three substituents independently selected
from the group consisting of halogen, cyano, C.sub.1 -C.sub.3
-alkoxy, and nitro; or benzyl substituted by one to three
substituents independently selected from the group consisting of
halogen, cyano, C.sub.1 -C.sub.3 -alkoxy, and nitro.
11. The compound according to claim 10, wherein R.sup.2 is phenyl
substituted by one to three substituents independently selected
from the group consisting of halogen, cyano, C.sub.1 -C.sub.3
-alkoxy, and nitro.
12. The compound according to claim 10, wherein R.sup.2 is benzyl
substituted by one to three substituents independently selected
from the group consisting of halogen, cyano, C.sub.1 -C.sub.3
-alkoxy, and nitro.
13. The compound according to claim 11, wherein R.sup.2 is phenyl
substituted by one to three C.sub.1 -C.sub.3 -alkoxy groups or by
one to three C.sub.1 -C.sub.3 -alkoxy groups in combination with
one to three halogens.
14. The compound according to claim 13, wherein R.sup.2 is phenyl
substituted by one to three C.sub.1 -C.sub.3 -alkoxy groups.
15. The compound according to claim 13, wherein R.sup.2 is phenyl
substituted by one to three C.sub.1 -C.sub.3 -alkoxy groups in
combination with one to three halogens.
16. The compound according to claim 12, wherein R.sup.2 is benzyl
substituted by one to three C.sub.1 -C.sub.3 -alkoxy groups or by
one to three C.sub.1 -C.sub.3 -alkoxy groups in combination with
one to three halogens.
17. The compound according to claim 16, wherein R.sup.2 is benzyl
substituted by one to three C.sub.1 -C.sub.3 -alkoxy groups.
18. The compound according to claim 16, wherein R.sup.2 is benzyl
substituted by one to three C.sub.1 -C.sub.3 -alkoxy groups in
combination with one to three halogens.
19. The compound according to claim 15, wherein the C.sub.1
-C.sub.3 -alkoxy group is methoxy and the halogen is fluorine.
20. The compound according to claim 17, wherein the C.sub.1
-C.sub.3 -alkoxy group is methoxy and the halogen is fluorine.
21. The compound according to claim 6, wherein R.sup.2 is C.sub.1
-C.sub.3 -alkoxy benzyl.
22. The compound according to claim 21, wherein R.sup.2 is
2-methoxy benzyl.
23. The compound according to claim 22, wherein R.sup.3 is R.sup.3a
--(CH.sub.2).sub.k --[CH(OR.sup.4)].sub.1 --CH.sub.2 --O--.
24. The compound according to claim 23, wherein R.sup.4 is
hydrogen, l is 1, k is 1, and R.sup.3a is methoxy.
25. The compound according to claim 22, wherein R is
H--[CH(OR.sup.4)].sub.2 --CH.sub.2 --O--CH.sub.2 --.
26. The compound according to claim 25, wherein R.sup.4 is
hydrogen.
27. The compound according to claim 26 which is
(R)-3-[(3S,4R,5R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-meth
oxy-naphthalen-2-ylmethoxy)-piperidin-3-ylmethoxy]-propane-1,2-diol
or a pharmaceutically acceptable salt thereof.
28. The compound according to claim 6, wherein R.sup.2 is benzyl
substituted by one C.sub.1 -C.sub.3 -alkoxy group and by one to
three halogen atoms.
29. The compound according to claim 28, wherein R.sup.2 is benzyl
substituted by one C.sub.1 -C.sub.3 -alkoxy group and by one or two
halogen atoms.
30. The compound according to claim 29, wherein the one or two
halogen atoms are fluorine.
31. The compound according to claim 30, wherein the C.sub.1
-C.sub.3 -alkoxy group is methoxy.
32. The compound according to claim 31, wherein the methoxy group
is at the 2-position on the benzyl ring.
33. The compound according to claim 32, wherein the benzyl ring is
substituted by one fluorine atom.
34. The compound according to claim 33, wherein R.sup.3 is R.sup.3a
--(CH.sub.2).sub.k --[CH(OR.sup.4)].sub.1 --CH.sub.2 --O--.
35. The compound according to claim 34, wherein R.sup.4 is
hydrogen, l is 1, k is 1, and R.sup.3a is methoxy.
36. The compound according to claim 35 which is
(R)-1-[(3S,4R,5R)-4-[4-[3-(5-fluoro-2-methoxy-benzyloxy)-propoxy]-phenyl]-
5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-3-yloxy]-3-methoxy-propan-2-
ol.
37. The compound according to claim 35 which is
(R)-1-[(3S,4R,5R)-4-[4-[3-(3-flouro-2-methoxy-benzyloxy)-propoxy]-phenyl]-
5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-3-yloxy]-3-methoxy-propan-2-
ol.
38. The compound according to claim 35 which is
(R)-1-[(3S,4R,5R)-4-[4-[3-(4-fluoro-2-methoxy-benzyloxy)-propoxy]-phenyl]-
5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-3-yloxy]-3-methoxy-propan-2-
ol.
39. The compound according to claim 32, wherein the benzyl ring is
substituted by two fluorine atoms.
40. The compound according to claim 39, wherein R.sup.3 is R.sup.3a
--(CH.sub.2).sub.k --[CH(OR.sup.4)].sub.1 --CH.sub.2 --O--.
41. The compound according to claim 6, wherein R.sup.2 is phenyl
substituted by one cyano group.
42. The compound according to claim 41, wherein R.sup.3 is R.sup.3a
--(CH.sub.2).sub.k --[CH(OR.sup.4)].sub.1 --CH.sub.2 --O--.
43. The compound according to claim 42, wherein R.sup.4 is
hydrogen, l is 1, k is 1, and R.sup.3a is methoxy.
44. The compound according to claim 43 which is
2-[3-[4-[(3S,4R,5R)-3-[(R)-2-hydroxy-3-methoxy-propoxy]-5-(4-methoxy-napht
halen-2-ylmethoxy)-piperidin-4-yl]-phenoxy]-propoxy]-benzonitrile.
45. The compound according to claim 6, wherein R.sup.2 is phenyl
substituted by one nitro group.
46. The compound according to claim 45, wherein R.sup.3 is R.sup.3a
--(CH.sub.2).sub.k --[CH(OR.sup.4)].sub.1 --CH.sub.2 --O--.
47. The compound according to claim 6, wherein R.sup.2 is phenyl
substituted by chlorine.
48. The compound according to claim 47, wherein R.sup.3 is R.sup.3a
--(CH.sub.2).sub.k --[CH(OR.sup.4)].sub.1 --CH.sub.2 --O--.
49. The compound according to claim 2, wherein R.sup.2 is
benzyl.
50. The compound according to claim 49, wherein R.sup.3 is
H--[CH(OR.sup.4)].sub.2 --CH.sub.2 --O--CH.sub.2 --.
51. The compound according to claim 50, wherein R.sup.4 is
hydrogen.
52. The compound according to claim 51 which is
(S)-3-[(3S,4R,5R)-4-[4-(3-benzyloxy-propoxy)-phenyl]-5-(naphthalen-2-ylmet
hoxy)-piperidin-3-ylmethoxy]-propane-1,2-diol.
53. The compound according to claim 51 which is
(R)-3-[(3S,4R,5R)-4-[4-(3-benzyloxy-propoxy)-phenyl]-5-(naphthalen-2-ylmet
hoxy)-piperidin-3-ylmethoxy]-propane-1,2-diol.
54. The compound according to claim 2, wherein R.sup.2 is
methoxy-benzyl.
55. The compound according to claim 54, wherein R.sup.3 is
H--[CH(OR.sup.4)].sub.2 --CH.sub.2 --O--CH.sub.2 --.
56. The compound according to claim 55, wherein R.sup.4 is
hydrogen.
57. The compound according to claim 56 which is
(S)-3-[(3S,4R,5R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(naphth
alen-2-ylmethoxy)-piperidin-3-ylmethoxy]-propane-1,2-diol.
58. The compound according to claim 56 which is
(R)-3-[(3S,4R,5R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(naphth
alen-2-ylmethoxy)-piperidin-3-ylmethoxy]-propane-1,2-diol.
59. The compound according to claim 6, wherein R.sup.2 is
methoxy-benzyl.
60. The compound according to claim 59, wherein R.sup.3 is R.sup.3a
--(CH.sub.2).sub.k --[CH(OR.sup.4)].sub.l --CH.sub.2 --O--.
61. The compound according to claim 60, wherein R.sup.4 is
hydrogen, l is 1, k is 1, and R.sup.3a is methoxy.
62. The compound according to claim 61 which is
(R)-1-methoxy-3-[(3S,4R,5R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]
-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-3-ylmethoxy]-propan-2-ol.
63. A compound of the formula: ##STR13##
wherein
R.sup.1 is naphthyl or naphthyl substituted by one to three C.sub.1
-C.sub.5 -alkoxy groups;
R.sup.2 is phenyl; phenyl substituted by one to three substituents
independently selected from the group consisting of halogen, cyano,
C.sub.1 -C.sub.3 -alkoxy, and nitro; benzyl; or benzyl substituted
by one to three substituents independently selected from the group
consisting of halogen, cyano, C.sub.1 -C.sub.3 -alkoxy, and
nitro;
R.sup.3 is H--[CH(OR.sup.4)].sub.2 --CH.sub.2 --O--CH.sub.2 --;
R.sup.4 is C.sub.1 -C.sub.3 -alkyl; or
a pharmaceutically acceptable salt thereof.
64. A compound of the formula: ##STR14##
wherein
R.sup.1 is naphthyl or naphthyl substituted by one to three C.sub.1
-C.sub.5 -alkoxy groups;
R.sup.2 is phenyl; phenyl substituted by one to three substituents
independently selected from the group consisting of halogen, cyano,
C.sub.1 -C.sub.3 -alkoxy, and nitro; benzyl; or benzyl substituted
by one to three substituents independently selected from the group
consisting of halogen, cyano, C.sub.1 -C.sub.3 -alkoxy, and
nitro;
R.sup.3 is R.sup.3a --(CH.sub.2).sub.k --[CH(OR.sup.4)].sub.l
--CH.sub.2 --O--;
R.sup.3a is hydrogen, hydroxy, imidazolyl, triazolyl, C.sub.1
-C.sub.3 -alkoxy, C.sub.1 -C.sub.3 -alkoxy-C.sub.2 -C.sub.3
-alkoxy, hydroxy-C.sub.2 -C.sub.3 -alkoxy, C.sub.1 -C.sub.3
-alkylamino or C.sub.1 -C.sub.3 -dialkylamino;
R.sup.4 is hydrogen or C.sub.1 -C.sub.3 -alkyl;
k is 1 or 2, when R.sup.3a is hydrogen, k is 0;
l is 1 or 2; or
a pharmaceutically acceptable salt thereof.
65. The compound according to claim 64, wherein R.sup.3a is
hydrogen and k is 0.
66. The compound according to claim 64, wherein R.sup.3a is
hydroxy, imidazolyl, triazolyl, C.sub.1 -C.sub.3 -alkoxy, C.sub.1
-C.sub.3 -alkoxy-C.sub.2 -C.sub.3 -alkoxy, hydroxy-C.sub.2 -C.sub.3
-alkoxy, C.sub.1 -C.sub.3 -alkylamino or C.sub.1 -C.sub.3
-dialkylamino.
67. The compound according to claim 66, wherein R.sup.3a is hydroxy
or C.sub.1 -C.sub.3 -alkoxy.
68. The compound according to claim 66, wherein R.sup.3a is
imidazolyl or triazolyl.
69. The compound according to claim 66, wherein R.sup.3a is C.sub.1
-C.sub.3 -alkoxy-C.sub.2 -C.sub.3 -alkoxy.
70. The compound according to claim 66, wherein R.sup.3a is
hydroxy-C.sub.2 -C.sub.3 -alkoxy.
71. The compound according to claim 66, wherein R.sup.3a is C.sub.1
-C.sub.3 -alkylamino or C.sub.1 -C.sub.3 -dialkylamino.
72. The compound according to claim 64, wherein R.sup.4 is C.sub.1
-C.sub.3 -alkyl.
73. The compound according to claim 64, wherein l is 1.
74. The compound according to claim 64, wherein l is 2.
75. The compound according to claim 64, wherein k is 1.
76. The compound according to claim 64, wherein k is 2.
77. The compound
(R)-1-methoxy-3-[(3S,4R,5R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]
-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-3-yloxy]-propan-2-ol
or a pharmaceutically acceptable salt thereof.
78. The compound
(S)-1-methoxy-3-[(3S,4R,5R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]
-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-3-yloxy]-propan-2-ol
or a pharmaceutically acceptable salt thereof.
79. A compound of the formula: ##STR15##
wherein
R.sup.1 is 4-methoxy-naphthalen-2yl;
R.sup.2 is 2-methoxy-benzyl;
R.sup.3 is R.sup.3a --(CH.sub.2).sub.k --[CH(OR.sup.4)].sub.l
--CH.sub.2 --O--;
R.sup.3a is 2-methoxy-ethoxy;
R.sup.4 is hydrogen;
k is 1;
l is 1; or
a pharmaceutically acceptable salt thereof.
80. The compound according to claim 79 which is
(R)-1-[(3S,4R,5R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-meth
oxy-naphthalen-2-ylmethoxy)-piperidin-3-yloxy]-3-(2-methoxy-ethoxy)-propan-
2-ol or a pharmaceutically acceptable salt thereof.
81. A compound of the formula: ##STR16##
wherein
R.sup.1 is 4-methoxy-naphthalen-2yl;
R.sup.2 is 2-methoxy-benzyl;
R.sup.3 is R.sup.3a --(CH.sub.2).sub.k --[CH(OR.sup.4)].sub.l
--CH.sub.2 --O--;
R.sup.3a is methylamino;
R.sup.4 is hydrogen;
k is 1;
l is 1; or
a pharmaceutically acceptable salt thereof.
82. The compound according to claim 81 which is
(R)-1-[(3S,4R,5R)-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-methox
y-naphthalen-2-ylmethoxy)-piperidin-3-yloxy]-3-methylamino-propan-2-ol
or a pharmaceutically acceptable salt thereof.
83. A compound of the formula: ##STR17##
wherein
R.sup.1 is 4-methoxy-naphthylen-2yl;
R.sup.2 is benzyl substituted by a methoxy group at the 2-position
and two florine atoms;
R.sup.3 is R.sup.3a --(CH.sub.2).sub.k --[CH(OR.sup.4)].sub.l
--CH.sub.2 --O--;
R.sup.3a is methoxy;
R.sup.4 is hydrogen;
k is 1;
l is 1; or
a pharmaceutically acceptable salt thereof.
84. The compound according to claim 83 which is
(R)-1-[(3S,4R,5R)-4-[4-[3-(4,5-difluoro-2-methoxy-benzyloxy)-propoxy]-phen
yl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-3-yloxy]-3-methoxy-propa
n-2-ol or a pharmaceutically acceptable salt thereof.
85. The compound according to claim 83 which is
(R)-1-[(3S,4R,5R)-4-[4-[3-(3,5-difluoro-2-methoxy-benzyloxy)-propoxy]-phen
yl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-3-yloxy]-3-methoxy-propa
n-2-ol or a pharmaceutically acceptable salt thereof.
86. A compound of the formula: ##STR18##
wherein
R.sup.1 is 4-methoxy-naphthylen-2yl;
R.sup.2 is benzyl substituted by a methoxy group at the 2-position
and two florine atoms;
R.sup.3 is R.sup.3a --(CH.sub.2).sub.k --[CH(OR)].sub.l --CH.sub.2
--O--;
R.sup.3a is hydroxy;
R.sup.4 is hydrogen;
k is 1;
l is 1; or
a pharmaceutically acceptable salt thereof.
87. The compound according to claim 86 which is
(R)-3-[(3S,4R,5R)-4-[4-[3-(4,5-difluoro-2-methoxy-benzyloxy)-propoxy]-phen
yl]-5-(4-methoxy-naphthalen-2-ylmethoxy]-piperidin-3-yloxy]-propane-1,2-dio
l or a pharmaceutically acceptable salt thereof.
88. The compound according to claim 86 which is
(R)-3-[(3S,4R,5R)-4-[4-[3-(3,5-difluoro-2-methoxy-benzyloxy)-propoxy]-phen
yl]-5-(4-methoxy-naphthalen-2-ylmethoxy]-piperidin-3-yloxy]-propane-1,2-dio
l or a pharmaceutically acceptable salt thereof.
Description
BACKGROUND OF THE INVENTION
The present invention relates to novel piperidine derivatives,
their manufacture and use as medicaments.
SUMMARY OF THE INVENTION
The subject invention provides compounds of the formula:
##STR2##
wherein
R.sup.1 is naphthyl or naphthyl substituted by one to three C.sub.1
-C.sub.5 -alkoxy groups;
R.sup.2 is phenyl; phenyl substituted by one to three substituents
independently selected from the group consisting of halogen, cyano,
C.sub.1 -C.sub.3 -alkoxy, and nitro; benzyl; or benzyl substituted
by one to three substituents independently selected from the group
consisting of halogen, cyano, C.sub.1 -C.sub.3 -alkoxy, and
nitro;
R.sup.3 is hydroxymethyl, imidazolylmethyl, triazolylmethyl,
H--[CH(OR.sup.4)].sub.2 -- CH.sub.2 --, H--[CH(OR.sup.4)].sub.2
--CH.sub.2 --O--CH.sub.2 --, or R.sup.3a --(CH.sub.2).sub.k
--[CH(OR.sup.4)].sub.1 --CH.sub.2 --O--;
R.sup.3a is hydrogen, hydroxy, imidazolyl, triazolyl, C.sub.1
-C.sub.3 -alkoxy, C.sub.1 -C.sub.3 -alkoxy-C.sub.2 -C.sub.3
-alkoxy, hydroxy-C.sub.2 -C.sub.3 -alkoxy, C.sub.1 -C.sub.3
-alkylamino or C.sub.1 --C.sub.3 -dialkylamino;
R.sup.4 is hydrogen or C.sub.1 -C.sub.3 -alkyl;
k is 1 or 2, when R.sup.3a is hydrogen, k is 0;
l is 1 or 2; or
and pharmaceutically acceptable salts thereof.
While the substituents are above listed collectively, all
combinations of the mentioned substituents are enabled and
described. For example, R.sup.1 can be naphthyl or naphthyl
substituted by one to three C.sub.1 -C.sub.5 -alkoxy groups,
preferably one C.sub.1 -C.sub.3 -alkoxy group, such as methoxy, and
in particular 4-methoxy-naphthalen-2yl.
Similarly, R.sup.2 can be phenyl, or benzyl, or phenyl substituted
by one to three substituents independently selected from the group
consisting of halogen, cyano, C.sub.1 -C.sub.3 -alkoxy, and nitro,
or benzyl substituted by one to three substituents independently
selected from the group consisting of halogen, cyano, C.sub.1
-C.sub.3 -alkoxy, and nitro. Preferred R.sup.2 s include phenyl
substituted by one to three substituents independently selected
from the group consisting of halogen, cyano, C.sub.1 -C.sub.3
-alkoxy, and nitro, and benzyl substituted by one to three
substituents independently selected from the group consisting of
halogen, cyano, C.sub.1 -C.sub.3 -alkoxy, and nitro. More preferred
R.sup.2 groups include phenyl substituted by one to three C.sub.1
-C.sub.3 -alkoxy groups or by one to three C.sub.1 -C.sub.3 -alkoxy
groups in combination with one to three halogens. Favorably,
R.sup.2 is phenyl substituted by one to three C.sub.1 -C.sub.3
-alkoxy groups or phenyl substituted by one to three C.sub.1
-C.sub.3 -alkoxy groups in combination with one to three halogens.
More preferred is where the C.sub.1 -C.sub.3 -alkoxy group is
methoxy and the halogen is fluorine. Favored situations include
R.sup.2 being 2-methoxy benzyl, 3-fluoro-2-methoxy-benzyl,
4-fluoro-2-methoxy-benzyl, 5-fluoro-2-methoxy-benzyl,
3,5-difluoro-2-methoxy-benzyl, and
4,5-difluoro-2-methoxy-benzyl.
R.sup.2 can also be benzyl substituted by one to three C.sub.1
-C.sub.3 -alkoxy groups or by one to three C.sub.1 -C.sub.3 -alkoxy
groups in combination with one to three halogens. Of these, it is
preferred that benzyl be substituted by one to three C.sub.1
-C.sub.3 -alkoxy groups or one to three C.sub.1 -C.sub.3 -alkoxy
groups in combination with one to three halogens, for example
2-methoxybenzyl and fluoro-2-methoxybenzyls, such as. It is
especially preferred where C.sub.1 -C.sub.3 -alkoxy group is
methoxy and the halogen is fluorine.
Preferred R.sup.3 s include hydroxymethyl, imidazolylmethyl,
triazolylmethyl, H--[CH(OR.sup.4)].sub.2 --CH.sub.2 --, and
H--[CH(OR.sup.4)].sub.2 --CH.sub.2 --O--CH.sub.2 --. Any of these
groups can be used. It is preferred, however, when R.sup.4 is
hydrogen. Also preferred is when R.sup.3 is R.sup.3a
--(CH.sub.2).sub.k --[CH(OR.sup.4)].sub.1 --CH.sub.2 --O--. In such
situations it is preferred that R.sup.3a is hydroxy or C.sub.1
-C.sub.3 -alkoxy, or imidazolyl or triazolyl, C.sub.1 -C.sub.3
-alkoxy-C.sub.2 -C.sub.3 -alkoxy, or R.sup.3a is hydroxy-C.sub.2
-C.sub.3 -alkoxy, or C.sub.1 -C.sub.3 -alkylamino or C.sub.1
-C.sub.3 -dialkylamino. A favored R.sup.3a is 2-methoxy-ethoxy.
Another is methylamino.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
The subject invention will now be described in terms of its
preferred embodiments. These embodiments are set forth to aid in
understanding the invention but are not to be construed as
limiting.
The invention relates to novel piperidine derivatives of general
formula I ##STR3##
wherein
R.sup.1 is naphthyl optionally substituted by one to three C.sub.1
-C.sub.5 -alkoxy groups;
R.sup.2 is phenyl or benzyl, optionally substituted by substituents
independently selected from one to three halogen, cyano, C.sub.1
-C.sub.3 -alkoxy and nitro groups;
R.sup.3 is hydroxymethyl, imidazolylmethyl, triazolylmethyl,
H--[CH(OR.sup.4)].sub.2 --CH.sub.2 --, or H--[CH(OR.sup.4)].sub.2
--CH.sub.2 --O--CH.sub.2 --, or R.sup.3a --(CH.sub.2).sub.k
--[CH(OR.sup.4)].sub.1 --CH.sub.2 --O--;
R.sup.3a is hydrogen, hydroxy, imidazolyl, triazolyl, C.sub.1
-C.sub.3 -alkoxy, C.sub.1 -C.sub.3 -alkoxy-C.sub.2 --C.sub.3
-alkoxy, hydroxy-C.sub.2 -C.sub.3 -alkoxy, C.sub.1 -C.sub.3
-alkylamino or C.sub.1 -C.sub.3 -dialkylamino;
R.sup.4 is hydrogen or C.sub.1 -C.sub.3 -alkyl;
k is 1 or 2, when R.sup.3a is hydrogen, k is 0;
l is 1 or 2; and
pharmaceutically acceptable salts thereof.
The present invention also relates to pharmaceutical compositions
comprising a compound of formula (I) and a pharmaceutically
acceptable carrier and/or adjuvant.
The piperidine derivatives of the present invention have an
inhibitory activity on the natural enzyme renin. Accordingly, they
can be used for the treatment of disorders which are associated
restenosis, glaucoma, cardiac infarct, high blood pressure and end
organ damage, e.g. cardiac insufficiency and kidney insufficiency.
In addition, the present invention relates to a method for the
prophylactic and/or therapeutic treatment of diseases which are
associated with restenosis, glaucoma, cardiac infarct, high blood
pressure and end organ damage, e.g. cardiac insufficiency and
kidney insufficiency, which method comprises administering a
compound of formula (I) to a human being or an animal. Furthermore,
the present invention relates to the use of such compounds for the
preparation of medicaments for the treatment of disorders which are
associated restenosis, glaucoma, cardiac infarct, high blood
pressure and end organ damage, e.g. cardiac insufficiency and
kidney insufficiency.
The present invention also relates to processes for the preparation
of the compounds of formula (I).
WO 97/09311 discloses piperidine derivatives of similar structure.
However, these compounds display a high lipophilicity.
Unless otherwise indicated the following definitions are set forth
to illustrate and define the meaning and scope of the various terms
used to describe the invention herein.
In this specification the term "lower" is used to mean a group
consisting of one to seven, preferably of one to four carbon
atom(s).
The term "alkyl" refers to a branched or straight chain monovalent
alkyl radical of one to seven carbon atoms, preferably one to four
carbon atoms, unless otherwise indicated. This term is further
exemplified by such radicals as methyl, ethyl, n-propyl, isopropyl,
n-butyl, s-butyl, t-butyl and the like.
The term "halogen" refers to fluorine, chlorine, bromine and
iodine, with chlorine and fluorine being preferred.
The term "alkoxy-" refers to the group R'--O--, wherein R' is
alkyl.
The term "alkylamino-" refers to the group HR'N--, wherein R' is
alkyl, The term "di-alkylamino" refers to the group R'R"N--,
wherein R' and R" are alkyl.
The term "pharmaceutically acceptable salts" embraces salts of the
compounds of formula (I) with inorganic or organic acids such as
hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid,
phosphoric acid, citric acid, formic acid, maleic acid, acetic
acid, succinic acid, tartaric acid, methanesulphonic acid,
p-toluenesulphonic acid and the like, which are non-toxic to living
organisms.
In detail, the present invention refers to compounds of formula (I)
##STR4##
wherein
R.sup.1 is naphthyl optionally substituted by one to three C.sub.1
-C.sub.5 -alkoxy groups;
R.sup.2 is phenyl or benzyl, optionally substituted by substituents
independently selected from one to three halogen, cyano, C.sub.1
-C.sub.3 -alkoxy and nitro groups;
R.sup.3 is hydroxymethyl, imidazolylmethyl, triazolylmethyl,
H--[CH(OR.sup.4)].sub.2 --CH.sub.2 --, or H--[CH(OR.sup.4)].sub.2
--CH.sub.2 --O--CH.sub.2 --, or R.sup.3a --(CH.sub.2).sub.k
--[CH(OR.sup.4)].sub.1 --CH.sub.2 --O--;
R.sup.3a is hydrogen, hydroxy, imidazolyl, triazolyl, C.sub.1
-C.sub.3 -alkoxy, C.sub.1 -C.sub.3 -alkoxy-C.sub.2 -C.sub.3
-alkoxy, hydroxy-C.sub.2 -C.sub.3 -alkoxy, C.sub.1 -C.sub.3
-alkylamino or C.sub.1 -C.sub.3 -dialkylamino;
R.sup.4 is hydrogen or C.sub.1 -C.sub.3 -alkyl;
k is 1 or 2, when R.sup.3a is hydrogen, k is 0;
l is 1 or 2; and
pharmaceutically acceptable salts thereof.
The compounds of formula I have at least three asymmetric carbon
atoms and can exist in the form of optically pure enantiomers,
racemates, diastereomer mixtures, diastereomeric racemates,
mixtures of diastereomeric racemates, in which the relative
configuration of the three piperidine ring substitutents has to be
all-trans as shown in formula I. The invention embraces all of
these forms. Racemates, diastereomeric mixtures, diastereomeric
racemates or mixtures of diastereomeric racemates can be separated
according to usual methods, e.g. by column chromatography,
thin-layer chromatography, HPLC and the like.
More particularly, the present invention relates to compounds of
the above formula (I), wherein R.sup.1 is naphthyl optionally
substituted by one C.sub.1 -C.sub.3 -alkoxy group. In a more
preferred embodiment R.sup.1 is naphthyl substituted by one C.sub.1
-C.sub.3 -alkoxy group, preferably methoxy. In a further preferred
embodiment, the alkoxy group is in meta position to the substituent
providing the connection with the piperidine residue of the
compounds of formula (I).
In a preferred embodiment, R.sup.2 is benzyl substituted by one to
three C.sub.1 -C.sub.3 -alkoxy groups or by one to three C.sub.1
-C.sub.3 -alkoxy groups in combination with one to three halogens.
Preferably the benzyl group is substituted by one C.sub.1 -C.sub.3
-alkoxy or by one C.sub.1 -C.sub.3 -alkoxy group in combination
with one to two halogens. The preferred C.sub.1 -C.sub.3 -alkoxy
group is methoxy, the preferred halogen is fluorine. In a more
preferred embodiment, the above mentioned alkoxy group is in ortho
position to the substituent providing the connection with the
phenylpiperidine of the compounds of formula (I).
In a preferred embodiment, the present invention comprises the
above compounds wherein R.sup.3a is hydroxy or C.sub.1 -C.sub.3
-alkoxy.
Particularly, the invention relates to compounds wherein R.sup.3 is
R.sup.3a --(CH.sub.2).sub.k --[CH(OR.sup.4)].sub.1 --CH.sub.2 --O--
or H--[CH(OR.sup.4)].sub.2 --CH.sub.2 --O--CH.sub.2 --.
In a preferred embodiment, the invention comprises the above
compounds wherein l is 1.
More particularly, the invention relates to compounds wherein
R.sup.3 is CH.sub.3 --O--CH.sub.2 --CH(OR.sup.4)--CH.sub.2 --,
H--[CH(OH)].sub.2 --CH.sub.2 --O--CH.sub.2 --, or HO--CH.sub.2
--CH(OR.sup.4)--CH.sub.2 --O--.
Particularly, the invention relates to the above compounds wherein
R.sup.4 is hydrogen.
The invention especially discloses compounds of formula (I) and
pharmaceutically acceptable salts thereof, selected from
1)
(R)-1-methoxy-3-[(3S,4R,5R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]
-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-3-yloxy]-propan-2-ol;
2)
(S)-1-methoxy-3-[(3S,4R,5R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]
-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-3-yloxy]-propan-2-ol;
3)
(R)-1-[(3S,4R,5R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-meth
oxy-naphthalen-2-ylmethoxy)-piperidin-3-yloxy]-3-(2-methoxy-ethoxy)-propan-
2-ol;
4)
(R)-1-[(3S,4R,5R)-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-4-methoxy
-naphthalen-2-ylmethoxy)-piperidin-3-yloxy]-3-methylamino-propan-2-ol;
5)
2-[3-[4-[(3S,4R,5R)-3-[(R)-2,3-dihydroxy-propoxy]-5-(4-methoxy-naphthalen-
2-ylmethoxy)-piperidin-4-yl]-phenoxy]-propoxy]-benzonitrile;
6)
2-[3-[4-[(3S,4R,5R)-3-[(R)-2-hydroxy-3-methoxy-propoxy]-5-(4-methoxy-napht
halen-2-ylmethoxy)-piperidin-4-yl]-phenoxy]-propoxy]-benzonitrile;
7)
2-[3-[4-[(3S,4R,5R)-3-[(R)-2-hydroxy-3-(2-methoxy-ethoxy)-propoxy]-5-4-met
hoxy-naphthalen-2-ylmethoxy)-piperidin-4-yl]-phenoxy]-propoxy]-benzonitrile
;
8)
(R)-3-[(3S,4R,5R)-5-(4-methoxy-naphthalen-2-ylmethoxy)-4-[4-[3-(2-nitro-ph
enoxy)-propoxy]-phenyl]-piperidin-3-yloxy]-propane-1,2-diol;
9)
(R)-1-[(3S,4R,5R)-5-(4-methoxy-naphthalen-2-ylmethoxy)-4-[4-[3-(2-nitro-ph
enoxy)-propoxy]-phenyl]-piperidin-3-yloxy]-3-[1,2,4]triazol-1-yl-propan-2-o
l;
10)
(R)-1-imidazol-1-yl-3-[(3S,4R,5R)-5-(4-methoxy-naphthalen-2-ylmethoxy)-4-[
4-[3-(2-nitro-phenoxy)-propoxy]-phenyl]-piperidin-3-yloxy)-propan-2-ol;
11)
(R)-3-[(3S,4R,5R)-4-[4-[3-(5-fluoro-2-methoxy-benzyloxy)-propoxy]-phenyl]-
5-(4-methoxy-naphthalen-2-ylmethoxy]-piperidin-3-yloxy]-propane-1,2-diol;
12)
(R)-3-[(3S,4R,5R)-4-[4-[3-(2-chloro-phenoxy)-propoxy]-phenyl]-5-(4-methoxy
-naphthalen-2-ylmethoxy)-piperidin-3-yloxy]-propane-1,2-diol;
13)
(R)-3-[(3S,4R,5R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-meth
oxy-naphthalen-2-ylmethoxy)-piperidin-3-ylmethoxy]-propane-1,2-diol;
14)
(3S,4R,5R)-[4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-methoxy-na
phthalen-2-ylmethoxy)-piperidin-3-yl]-methanol;
15)
(3S,4R,5R)-3-imidazol-1-ylmethyl-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-ph
enyl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine
dihydrochloride;
16)
(S)-3-[(3S,4R,5R)-4-[4-(3-benzyloxy-propoxy)-phenyl]-5-(naphthalen-2-ylmet
hoxy)-piperidin-3-ylmethoxy]-propane-1,2-diol;
17)
(R)-3-[(3S,4R,5R)-4-[4-(3-benzyloxy-propoxy)-phenyl]-5-(naphthalen-2-ylmet
hoxy)-piperidin-3-ylmethoxy]-propane-1,2-diol;
18)
(S)-3-[(3S,4R,5R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(naphth
alen-2-ylmethoxy)-piperidin-3-ylmethoxy]-propane-1,2-diol;
19)
(R)-3-[(3S,4R,5R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(naphth
alen-2-ylmethoxy)-piperidin-3-ylmethoxy]-propane-1,2-diol;
20)
(R)-1-[(3S,4R,5R)-4-[4-[3-(5-fluoro-2-methoxy-benzyloxy)-propoxy]-phenyl]-
5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-3-yloxy]-3-methoxy-propan-2-
ol;
21)
(R)-1-[(3S,4R,5R)-4-[4-[3-(3-fluoro-2-methoxy-benzyloxy)-propoxy]-phenyl]-
5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-3-yloxy]-3-methoxy-propan-2-
ol;
22)
(R)-1-[(3S,4R,5R)-4-[4-[3-(4-fluoro-2-methoxy-benzyloxy)-propoxy]-phenyl]-
5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-3-yloxy]-3-methoxy-propan-2-
ol;
23)
(R)-1-[(3S,4R,5R)-4-[4-[3-(4,5-difluoro-2-methoxy-benzyloxy)-propoxy]-phen
yl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-3-yloxy]-3-methoxy-propa
n-2-ol;
24)
(R)-1-[(3S,4R,5R)-4-[4-[3-(3,5-difluoro-2-methoxy-benzyloxy)-propoxy]-phen
yl]-5-(4-
methoxy-naphthalen-2-ylmethoxy)-piperidin-3-yloxy]-3-methoxy-propan-2-ol;
and
25)
(R)-1-methoxy-3-[(3S,4R,5R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]
-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-3-ylmethoxy]-propan-2-ol.
An especially preferred compound is
(R)-1-methoxy-3-[(3S,4R,5R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]
-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-3-yloxy]-propan-2-ol
and pharmaceutically acceptable salts thereof.
A further especially preferred compound is
(R)-3-[(3S,4R,5R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-meth
oxy-naphthalen-2-ylmethoxy)-piperidin-3-ylmethoxy]-propane-1,2-diol
and pharmaceutically acceptable salts thereof.
A further especially preferred compound is
(R)-3-[(3S,4R,5R)-4-[4-[3-(5-fluoro-2-methoxy-benzyloxy)-propoxy]-phenyl]-
5-(4-methoxy-naphthalen-2-ylmethoxy]-piperidin-3-yloxy]-propane-1,2-diol
and pharmaceutically acceptable salts thereof.
A further especially preferred compound is
(R)-1-[(3S,4R,5R)-4-[4-[3-(5-fluoro-2-methoxy-benzyloxy)-propoxy]-phenyl]-
5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-3-yloxy]-3-3-methoxy-propan-
2-ol and pharmaceutically acceptable salts thereof.
A further especially preferred compound is
(R)-1-methoxy-3-[(3S,4R,5R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]
-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-3-ylmethoxy]-propan-2-ol
and pharmaceutically acceptable salts thereof.
The invention also relates to pharmaceutical compositions
comprising a compound as defined above and a pharmaceutically
acceptable carrier and/or adjuvant. The pharmaceutical compositions
may comprise in addition one or more compounds active against
restenosis, glaucoma, cardiac infarct, high blood pressure and end
organ damage, e.g. cardiac insufficiency and kidney insufficiency.
Examples for these additional compounds are angiotensin converting
enzyme-inhibitors) e.g. captopril, lisinopril, enalapril and
cilazapril; angiotensin-(1)-receptor antagonists, e.g. lorsartan
and valsartan; diuretica, e.g. hydrochlorothiazide, mefrusid and
furosemid; endothelin receptor antagonists, e.g. bosentan;
endothelin converting enzyme inhibitors or neutral endopeptidase
inhibitors; calcium channel blockers (antagonists), e.g.
nifedipine, verapamil, and diltiazem; nitrates, e.g.
glyceroltrinitrates (nitroglycerin) and isosorbid-dinitrates;
beta-receptor blockers, e.g. carvedilol, alprenolol and
propranolol; alpha-1 adrenoceptor antagonists, e.g. prazosin and
terazosin; and reserpin.
A further embodiment of the present invention refers to the use of
a compound as defined above for the preparation of medicaments for
the treatment or prophylaxis of restenosis, glaucoma, cardiac
infarct, high blood pressure and end organ damage, e.g. cardiac
insufficiency and kidney insufficiency.
An additional embodiment of the invention relates to a method for
the prophylactic and/or therapeutic treatment of disorders in which
renin plays a significant pathological role, especially restenosis,
glaucoma, cardiac infarct, high blood pressure and end organ
damage, e.g. cardiac insufficiency and kidney insufficiency which
method comprises administering a compound as defined above to a
human being or an animal.
The compounds as defined above may be manufactured by cleaving off
the protecting group P.sup.1 and optionally hydroxy protecting
groups which may be present in compounds of formula (II)
##STR5##
wherein P.sup.1 represents a NH-protecting group and the remaining
symbols have the significance given above wherein hydroxy groups
which may be contained in R.sup.1, R.sup.2, and R.sup.3 may
optionally be present in protected form. If desired, reactive
groups may be functionally modified in the thus-obtained compound
of formula I (e.g. into esters) and/or converted into a
pharmaceutically usable salt.
The cleavage of a protecting group P.sup.1 and hydroxy protecting
groups which may be present can be carried out in a manner known
per se. Examples of protecting groups P.sup.1 are usual amino
protecting groups such as tert-butoxycarbonyl, benzyloxycarbonyl,
allyloxycarbonyl, vinyloxycarbonyl, alkylsilylalkyloxycarbonyl such
as 2-(trimethylsilyl)ethoxycarbonyl, and trichloroethoxycarbonyl.
Examples of hydroxy protecting groups are ether-protecting groups
such as tetrahydropyranyl, allyl, 2-(trimethylsilyl)ethoxymethyl,
trityl, tert-butyldimethylsilyl or ester protecting groups such as
acetyl. Examples of diol protecting groups are cyclic ether
protecting groups such as isopropylidene or benzylidene.
The cleavage of these protecting groups is effected by acidic or
basic hydrolysis, by reductive methods or by means of Lewis acids
or fluoride salts. A solution of a mineral acid such as
hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid
and the like in an inert solvent or solvent mixture is
advantageously used for the acidic hydrolysis. Suitable solvents
are alcohols such as methanol or ethanol, ethers such as
tetrahydrofuran or dioxan, chlorinated hydrocarbons such as
methylene chloride, and the like. Alkali metal hydroxides and
alkali metal carbonates such as potassium hydroxide or sodium
hydroxide or potassium carbonate or sodium carbonate, organic
amines such as piperidine, and the like can be used for the basic
hydrolysis. Inert organic solvents as referred to above for the
acidic hydrolysis can be used as solubilizers. The reaction
temperature for the acidic and basic hydrolysis can be varied in a
range from 0.degree. C. to the reflux temperature, with the
reaction preferably being carried out at between about 0.degree. C.
and room temperature. The tert-butoxycarbonyl group is conveniently
cleaved off with hydrochloric acid, hydrogen chloride,
trifluoroacetic acid or formic acid in the presence or absence of
an inert solvent. Furthermore, the tert-butoxycarbonyl group can be
cleaved off by means of anhydrous zinc bromide in the presence of
an inert solvent, preferably methylene chloride. The cleavage of
the trichloroethoxycarbonyl group can be advantageously effected
reductively with zinc in glacial acetic acid. The reaction
temperature can lie in a range of 0.degree. C. to 40.degree. C.,
with the reaction preferably being carried out at room temperature.
The cleavage of the 2-(trimethylsilyl)ethoxycarbonyl group can be
effected by means of fluoride ions in the presence of an inert
solvent such as acetonitrile, dimethyl sulphoxide,
dimethylformamide or tetrahydrofuran, preferably by means of
tetrabutylammonium fluoride in tetrahydrofuran, at temperatures
from about 0.degree. C. to about room temperature.
The compounds of formula (II) are novel and are also an object of
the invention. Their preparation is described in more detail
hereinafter in Schemes 1-4 and in the Examples. ##STR6##
Derivatives of general formula 2 in which P.sup.1* has, in addition
to the meanings of P.sup.1, the meaning of benzyl or (R)- or
(S)-2-phenethyl, can be obtained by alkylation of the 3-hydroxy
function in a suitably N,4'--O--di-protected
4-(4-hydroxy-phenyl)-1,2,3,6-tetrahydro-pyridin-3-ol of the general
formula 1. The alkylation can be performed in solvents as ethers,
like tetrahydrofuran and 1,2-dimethoxyethane, N,N-dimethylformamide
or dimethylsulfoxide with aliphatic chlorides, bromides, iodides,
tosylates or mesylates in the presence of a base like sodium
hydride or potassium tert-butoxide. The alkylating agents used can
contain optionally suitably protected functional groups which allow
further structural modifications at a later stage of the synthesis.
Hydroboration of the ether compounds formed (general formula 2)
followed by subsequent basic oxidative working-up produces
compounds of the general formula 3 with high diastereoselectivity,
the isomer bearing only equatorial substituents at the piperidine
ring being formed almost exclusively. The absolute stereochemistry
at carbon 3 of the piperidine ring remains unaffected during the
transformation of compounds 1 to compounds 3. The hydroboration can
be effected according to methods known per se, for example in a
solvent which is inert under the reaction conditions, such as an
ether, e.g. 1,2-dimethoxyethane, at a temperature between about
0.degree. C. and 70.degree. C., and with a diborane-containing or
diborane-liberating reagent such as e.g. borane in tetrahydrofuran
or a mixture of sodium borohydride and boron trifluoride etherate.
The carboboranes which are formed as intermediates can be converted
into the secondary alcohols of general formula 3 by reaction with
bases, e.g. potassium hydroxide, and an oxidizing agent, e.g.
hydrogen peroxide, at a temperature between about room temperature
and 120.degree. C. Removal of the N- and O-protective functions and
reintroduction of a optionally different N-protective group
(P.sup.3), e.g. a N-Boc group, by well established procedures as
e.g.: hydrogenolysis with hydrogen in the presence of a palladium
catalyst followed by introduction of the Boc group with
di-tert-butyldicarbonate in dioxan/water converts compounds of the
general formula 3 into a compound of the general formula 4 bearing
a phenolic and an aliphatic OH-function which can be derivatized
selectively.
Selective derivatization of the phenolic function in compounds of
general formula 4 can be performed by alkylation reactions using
aliphatic chlorides, bromides, iodides, tosylates or mesylates in
the presence of a base like potassium carbonate in solvents such as
an ether like tetrahydrofuran, in N,N-dimethylformamide,
dimethylsulfoxide, acetone, methyl-ethyl-ketone, or pyridine at
temperatures between 0.degree. C. and 140.degree. C. leading to
compounds of the general formula 5. The substituent introduced can
function as a protecting group, being e.g. an allyl ether, or can
be a unit which contains optionally suitably protected functional
groups to allow further structural modifications at a later stage
of the synthesis or consist of the whole substituent desired.
Derivatization at the secondary hydroxy function of the piperidine
ring can than be performed in solvents as ethers, like
tetrahydrofuran or 1,2-dimethoxyethane, or in N,N-dimethylformamide
or dimethylsulfoxide in the presence of an anion-forming base, like
sodium hydride or potassium tert-butoxide, and a suitable
alkylating agent, preferentially an aryl methyl chloride, bromide,
mesylate or tosylate at temperatures between 0.degree. C. and
40.degree. C. thus giving compounds of the general formula 6. If
R.sup.21 represents allyl, then this protective function can be
replaced by a suitable substituent at any stage of the synthesis,
e.g. by treatment with a palladium catalyst as palladium-II-acetate
in the presence of triphenylphosphine and lithiumborohydride in a
solvent like tetrahydrofuran or 1,2-dimethoxyethane followed by an
alkylation procedure as described above. ##STR7##
In case R.sup.31 contains a diol function protected as
1,3-dioxolane derivative, then the free diol can be liberated using
hydrochloric acid in methanol, a procedure which also liberates the
secondary amino function of the piperidine ring, if protected with
a Boc-protective group. The Boc-protective function can optionally
be reintroduced using di-tert-butyl-dicarbonate in a solvent, like
a mixture of water and dioxane, methanol or acetonitril, in the
presence of a base, like sodium hydrogencarbonate or triethylamine,
leading to compounds of the general formula 7. A primary/secondary
diol unit can be modified by transformation of e.g. the primary
hydroxy function into a leaving group, e.g. a tosyloxy- or a
mesyloxy-group. Selective tosylation of a primary hydroxy function
in the presence of a secondary hydroxy function can be performed
with tosyl chloride in a solvent like pyridine. If an excess of
tosyl chloride is used, a short reaction time can prevent the
formation of substantial amounts of the undesired ditosylate.
Treatment of the monotosylate with base, e.g. with sodium hydroxide
in dimethylsulfoxide, affords the corresponding oxiran 8.
Optionally, the oxiran 8 can be prepared from the corresponding
diol in a one step procedure by using reagents as
diethoxytriphenylphosphorane (DTPP) in a solvent like
dichloromethane or tetrahydrofuran, ether or 1,2-dimethoxyethane at
temperatures between 40.degree. C. and 100.degree. C. under
essentially neutral conditions (P. L. Robinson; J. W. Kelly; S. A.
Evans, J. R. Phosphorus and Sulfur 1986, 26, 12-24). The oxiran
opens regioselectively at the less hindered site when reacted with
an alkali salt of an alcohol as methanol or methoxyethanol or an
alkali salt of a heterocycle as [1,2,4]triazol or imidazol in a
solvent like N,N-dimethylformamide, dimethylsulfoxide or an ether
like tetrahydrofuran to give compounds of the general formula 9.
Final removal of e.g. a Boc-protective group can be performed in
the presence of acids such as hydrochloric, hydrobromic, sulfuric,
phosphoric, trifluoroactic acid in a variety of solvents such as
alcohols and alcohol/water mixtures, ethers and chlorinated
hydrocarbons. The Boc-protective group can also be removed with
anhydrous zinc bromide in inert solvents such as dichloromethane
leading to compounds of the general formula 10. ##STR8##
Derivatives of general formula 14 in which P.sup.1* has, in
addition to the meanings of P.sup.1, the meaning of benzyl can be
obtained in accordance with Scheme 3 from the compound of general
formula 11 (with R being e.g. methyl or ethyl; commercially
available compounds, e.g. Aldrich) by reduction to the diol
analogously to the process described by E. Jaeger and J. H. Biel in
J. Org. Chem. 30(3), 740-744 (1965), followed by the introduction
of a suitable protecting group for the primary alcohol, e.g.
tert-butyldimethylsilyl, tert-butyldiphenylsilyl, preferably
trityl. The oxidation of the secondary alcohol of general formula
13 can be carried out in manner known per se, e.g. by using oxalyl
chloride and dimethyl sulphoxide as described by A. J. Mancuso and
D. Swern in Synthesis 1981, 165, to yield the ketone of general
formula 14.
Compounds of general formula 16 can be obtained by reacting
compounds of general formula 14 in a manner known per se with
metal-organic derivatives, preferably lithium or magnesium
derivatives, prepared from compounds of general formula 15 wherein
P.sup.2 represents lower-alkoxy, preferably methoxy, or benzyloxy.
The reaction with such a metal-organic compound is effected
according to methods known per se, for example in a solvent which
is inert under the reaction conditions, such as an ether, at a
temperature between about -78.degree. C. and 75.degree. C.
The compounds of general formula 17 can be obtained therefrom in
the presence of an acid or another water-cleaving reagent,
optionally in the presence of a base, in an organic solvent. As
acids there come into consideration e.g. hydrochloric acid,
trifluoroacetic acid or p-toluenesulphonic acid, and as the
water-cleaving reagent there can be used e.g. phosphorus
oxytrichloride in pyridine. The reaction temperature lies between
0-120.degree. C.; as solvents there can be used e.g. toluene,
dimethylformamide or alcohols.
Compounds of general formula 18 can be obtained from compounds of
general formula 17 by hydroboration and subsequent basic oxidative
working-up. The hydroboration can be effected according to methods
known per se, for example in a solvent which is inert under the
reaction conditions, such as an ether, e.g. 1,2-dimethoxyethane, at
a temperature between about 0.degree. C. and 70.degree. C., and
with a diborane-containing or diborane-liberating reagent such as
e.g. borane in tetrahydrofuran or a mixture of sodium borohydride
and boron trifluoride etherate. The carboboranes which are formed
as intermediates can be converted into the secondary alcohols of
general formula 18 by reaction with bases, e.g. potassium
hydroxide, and an oxidizing agent, e.g. hydrogen peroxide, at a
temperature between about room temperature and 120.degree. C.
Hydroboration of compounds of the general formula 17, followed by
basic oxidative working-up produces compounds of the general
formula 18 with high diastereoselectivity; the isomer bearing only
equatorial substituents at the piperidine ring is almost
exclusively formed.
Compounds of formula 18 in which P.sup.2 is lower-alkoxy can be
converted into compounds of general formula 19 by an alkyl-aryl
ether cleavage. The ether cleavage is effected according to methods
known per se by, preferably starting from compounds in which
P.sup.2 has the meaning methoxy, reacting the alkyl-aryl ether with
mineral acids such as hydrobromic acid or hydriodic acid or
preferably with Lewis acids such as boron trichloride or boron
tribromide in a solvent which is inert under the reaction
conditions, such as e.g. a halogenated hydrocarbon, at a
temperature between about -10.degree. C. and room temperature.
Under these conditions, the protecting group P.sup.4 which,
preferably, has the meaning trityl, tert-butyl-diphenylsilyl or
tert-butyl-dimethylsilyl, is also cleaved.
Compounds of formula 19 in which P.sup.2 is benzyl can be converted
into compounds of general formula 20 by hydrogenolysis with
hydrogen in the presence of a palladium catalyst in an inert
solvent or solvent mixture. Suitable solvents are alcohols, such as
methanol or ethanol, ethyl acetate and the like, at temperatures
from about 0.degree. C. to 40.degree. C.
Compounds of formula 18 in which P.sup.2 is benzyl, P.sub.1 is
benzyl and P.sup.4 is trityl can directly be converted into
compounds of general formula 20 by hydrogenolysis with hydrogen in
the presence of a palladium catalyst under conditions mentioned
above. ##STR9##
After removal of the N- and O-protecting functions compounds of
formula 21 can be obtained by reintroduction of an optionally
different N-protecting group, preferably tert-butoxycarbonyl, by
well established procedures. The introduction of
tert-butoxycarbonyl can be selectively effected by the reaction of
compounds of general formula 20 with di-tert-butyldicarbonate in
dioxan/water at temperatures from about -10.degree. C. to room
temperature.
Compounds of general formula 21 can be used as starting materials
for the preparation of compounds of general formula 22 in which
R.sup.22 is the group --(CH.sub.2).sub.3 --O--R.sup.2 with the
meanings referred to above. The linkage of the group
--(CH.sub.2).sub.3 --O--R.sup.2 can be effected selectively by
reaction with a derivative of the group to be introduced which
carries a suitable leaving group. The selective linkage with the
phenolic alcohol is effected according to alkylation methods which
are known per se in the presence of a base such as potassium
carbonate. Chlorides, bromides, iodides, tosylates or mesylates
come into consideration as alkylating agents. The reaction is
effected in a solvent which is inert under the reaction conditions,
such as e.g. an ether such as tetrahydrofuran or an aromatic
hydrocarbon such as e.g. toluene, pyridine, acetone or methyl ethyl
ketone, at a temperature between about 0.degree. C. and 100.degree.
C.
Compounds of general formula 23 can be obtained by introduction of
a protecting group P.sup.4 selective for primary alcohols and
selectively cleavable at an appropriate later stage of the reaction
sequence in presence of the N-protecting group and the other
functionalities. Examples of such hydroxy protecting groups are
tert-butyldimethylsilyl, tert-butyldiphenylsilyl, and preferably
trityl.
Compounds of general formula 24 can be obtained from 23 by
alkylation with a compound which yields the group --CH.sub.2
--R.sup.1. The alkylation of the secondary alcohol is effected
according to methods known per se, for example in a solvent which
is inert under the reaction conditions, such as an ether, e.g.
tetrahydrofuran or 1,2-dimethoxyethane, or dimethylformamide, with
the aid of an alcoholate-forming base, e.g. sodium hydride, at a
temperature between about 0.degree. C. and 40.degree. C. and using
a halide, preferably chloride or bromide, or a sulfonic acid ester,
e.g. a mesylate or tosylate, as the compound which yields the group
--CH.sub.2 --R.sup.1.
Compounds of general formula 25 can be obtained from 24 by
selective cleavage of protecting group P.sup.4. The cleavage of
these protecting groups is effected by acidic hydrolysis or by
means of Lewis acids. The trityl group is conveniently cleaved off
with a mixture of trifluoroacetic acid and trifluoroacetic acid
anhydride in the presence of an inert solvent, preferably
dichloromethane in a very short time at temperatures from about
-10.degree. C. to 0.degree. C. The cleavage of the silyl protecting
groups can be effected by means of fluoride ions in the presence of
an inert solvent such as acetonitril, dimethylsulphoxide,
N,N-dimethylformamide or tetrahydrofuran, preferably by means of
tetrabutylammonium fluoride in tetrahydrofuran, at temperatures
from about 0.degree. C. to about room temperature.
Compounds of general formula 26 can be obtained from 25 by
alkylation with a compound which yields the group R.sup.33, where
R.sup.33 has the meaning of H--[CH(OR.sup.4)].sub.2 --CH.sub.2 --.
The alkylation of the primary alcohol is effected according to
methods known per se, for example in a solvent which is inert under
the reaction conditions, such as an ether, e.g. tetrahydrofuran or
1,2-dimethoxyethane, or dimethylformamide, with the aid of an
alcoholate-forming base, e.g. sodium hydride, at a temperature
between about 0.degree. C. and 40.degree. C. and using a halide,
preferably chloride or bromide, or a sulfonic acid ester, e.g. a
mesylate or tosylate, as the compound which yields the group
R.sup.33. Optionally, the alkylating agents used can contain
suitably protected functional groups which allow further structural
modifications at a later stage of the reaction sequence. As
alkylating agent there comes into consideration e.g. allylbromide
which then can be hydroxylated according to methods known per se,
or
(R)-(-)-2,2-dimethyl-4-(hydroxymethyl)-[1,3]dioxolane-p-toluenesulfonate.
In case the diol function is protected as a 1,3-dioxolane
derivative, then the free diol can be liberated using hydrochloric
acid in methanol, a procedure which also liberates the secondary
amino function of the piperidine ring, if protected by a Boc-group.
The Boc-protective function can optionally be reintroduced using
di-tert-butyl-dicarbonate in a solvent, like a mixture of water and
dioxane, methanol or acetonitril, in the presence of a base, like
sodium hydrogencarbonate or triethylamine. The resulting
primary/secondary diol unit can be manipulated analogously as
described for compounds of the general formula 8, 9 and 10.
Compounds of general formula 27 in which R.sup.34 is imidazolyl or
triazolyl can be obtained from compounds of general formula 25. The
reaction is effected according to methods known per se, for example
in a solvent which is inert under the reaction conditions, such as
an ether, e.g. tetrahydrofuran or 1,2-dimethoxyethane, or
N,N-dimethylformamide, with the aid of an anion-forming base, e.g.
sodium hydride, at a temperature between about 0.degree. C. and
40.degree. C. and using a sulfonic acid ester, e.g. a tosylate,
mesylate or triflate, as the activated derivative of the primary
alcohol.
Compounds of general formula 27 where R.sup.34 has the meaning of
H--[(CH(OR.sup.4)].sub.2 -- can be obtained by transforming
compounds of general formula 25 into the corresponding halides,
preferably into chlorides or bromides, reacting them with
metallorganic reagents according to methods known per se, e.g. with
vinylmagnesium bromide in an inert solvent like tetrahydrofuran,
and hydroxylating them according to methods known per se.
Piperidines of general formula 25, 26 and 27 can also be obtained
in optically pure form. Separation into antipodes can be effected
according to methods known per se, preferably at an early stage of
the synthesis by salt formation with an optically active acid. For
example, compounds of general formula 18 in which P.sup.1* has the
meaning of benzyl can be obtained in their optically pure form by
treatment with (+)- or (-)-mandelic acid and separation of the
diastereomeric salts by fractional crystallization. Or, at a later
stage, by derivatization with a chiral auxiliary substance such as,
for example, (+)- or (-)-camphamoyl chloride and separation of the
diastereomeric products by chromatography and/or crystallization
and subsequent cleavage of the bond to the chiral auxiliary
substance. In order to determine the absolute configuration of the
piperidine derivative obtained, the pure diastereomeric salts and
derivatives can be analyzed by conventional spectroscopic methods,
with X-ray spectroscopy on single crystals being an especially
suitable method.
Starting compounds 1 are known in the art and may be prepared
according to the methods described in WO97/09311 or according to a
reaction wherein a compound of formula 28 or a salt thereof
##STR10##
wherein A is arylene; R.sup.1' is --C*R.sup.3' R.sup.4' R.sup.5' ;
R.sup.2' is --O-alkyl, --O-cycloalkyl, --O-alkenyl, or a group
--OP.sup.2 as defined above, --O-aryl, --O-aralkyl,
--O-aralkoxyalkyl, --O-alkylsulfonyl, --O-arylsulfonyl, chlorine,
bromine or iodine; R.sup.3' is hydrogen; R.sup.4' is aryl; R.sup.5'
is alkyl, cycloalkyl, aryl, alkoxyalkyl or hydroxyalkyl; and,
wherein C* is an asymmetric carbon atom; is epoxidated, optionally
followed by isolation of the desired stereoisomer, resulting in a
compound of formula 29 ##STR11##
The reaction may be performed by transforming a compound of general
formula 28 into a halohydrine which by treatment with base gives
the epoxide of general formula 29.
In detail, examples for compounds which are known for use in such
epoxidation reactions are halogens and organic bromo-compounds such
as N-bromosuccinimide, dibromoisocyanurate and
1,3-dibromo-5,5-dimethylhydantoin. Preferred is bromine, especially
in the presence of an acid, preferably HBr and chemical equivalents
thereof. Inert solvents taken alone or in combination can be used,
particularly, solvents which are known for their utilization in
epoxidation reactions. Examples of such solvents are straight or
cyclic ethers dimethylether, diethylether, tetrahydrofuran and
monoglyme or diglyme alone or in such a combination that a
sufficient miscibility with water is given. A preferred solvent is
dioxane. Preferred is the above reaction in the presence of an
acid. Examples of such acids are optically active or inactive acids
such as the hydrohalic acids, sulfonic acids and H.sub.2 SO.sub.4.
Particularly preferred is HBr. In general the above reaction can be
performed in a wide pH range. Preferred is a pH range from about 1
to 4 and particularly preferred is a pH range from about 1,5 to 3.
A temperature range of from about -20.degree. C. to the boiling
point of the solvent is suitable for the reaction of the present
invention. The preferred temperature range is between about
-20.degree. C. to about 20.degree. C. preferably from about
0.degree. C. to about 5.degree. C.
The above reaction is followed by addition of a base such as NaOH,
KOH, or a nitrogen-base such as triethylamine. Preferred is the use
of NaOH or KOH. The temperature range for the addition of the base
is between -20.degree. C. and the boiling point of the solvent.
Preferred is a temperature range between -20.degree. C. and
20.degree. C. Particularly preferred is the addition of the base
between 0.degree. C. and 5.degree. C. In case the epoxidising agent
reacts with a compound of the formula 28 without addition of an
acid, the epoxide can be obtained without using a base.
According to the above process compounds of formula 29 are formed
as a mixture of stereoisomers and particularly as a mixture of
diastereomers, or only one of the diastereomers is formed. In a
preferred aspect one of the diastereomers is formed preferably.
Optionally the desired stereoisomer especially diastereomer can be
isolated by methods known in the art such as crystallisation,
chromatography or distillation, preferably crystallisation or
chromatography. These methods also include the formation of salts
or derivatives of compounds of the formula 29 and in a following
step the separation of these salts or derivatives by the above
methods. These methods, especially methods for the separation of
diastereoisomers are well known in the art and are for example
described in Houben-Weyl, Methods of Organic Chemistry (pp. Vol.
E21, p. 81, 91).
Allylic alcohols of general formula 1 can be obtained from
compounds of general formula 29 by rearrangement of the epoxide by
a base. A preferred method is the reaction with a metal alcoholate
such as potassium t-butoxide, aluminium isopropoxide, titanium (IV)
t-butoxide, with a lithium amide such as lithium diisopropylamide
or with an organolithium compound such as phenyllithium,
sec-butyllithium or methyllithium to give a compound of the general
formula 1.
Moreover, a preferred aspect of the above process is the reaction
of a compound of the formula 29 or a salt thereof, with
phenyllithium. Particularly preferred is the above reaction,
wherein the desired stereoisomer of a compound of the formula 29
reacts with phenyllithium. Solvents for this reaction taken alone
or in combination are for example: ethers such as tetrahydrofuran,
diethyl ether, or tert-butyl methyl ether, aromatic hydrocarbons
such as toluene or chlorobenzene or pyridine. The solvent, which is
preferred, depends on the reagent. In the case of phenyllithium as
the reagent, tert-butyl methyl ether is a particularly preferred
solvent.
The rearrangement of the epoxide can be performed in a temperature
range from about -40.degree. C. up to the boiling of the solvent.
Preferred is a temperature range from about -25.degree. C. up to
0.degree. C. Particularly preferred is a temperature of about
-15.degree. C.
The present invention relates to all compounds of formula (I),
whenever prepared by one of the processes described above.
The invention also relates to compounds as defined above for the
treatment of diseases which are associated with restenosis,
glaucoma, cardiac infarct, high blood pressure and end organ
damage, e.g. cardiac insufficiency and kidney insufficiency.
The compounds of formula I and their pharmaceutically usable salts
have an inhibitory activity on the natural enzyme renin. The latter
passes from the kidneys into the blood and there brings about the
cleavage of angiotensinogen with the formation of the decapeptide
angiotensin I which is then cleaved in the lungs, the kidneys and
other organs to the octapeptide angiotensin II. Angiotensin II
increases blood pressure not only directly by arterial
constriction, but also indirectly by the liberation of the sodium
ion-retaining hormone aldosterone from the adrenal gland, with
which is associated an increase in the extracellular fluid volume.
This increase is attributed to the action of angiotensin II itself
or to that of the hepapeptide angiotensin III which is formed
therefrom as a cleavage product. Inhibitors of the enzymatic
activity of renin bring about a decrease in the formation of
angiotensin I and as a consequence of this the formation of a
smaller amount of angiotensin II. The reduced concentration of this
active peptide hormone is the direct reason for the blood
pressure-lowering activity of renin inhibitors.
The in-vitro potency of renin inhibitors can, as described by W.
Fischli et al. in Hypertension, Vol. 18 (1), 22-31 (1991) or
Hypertension Vol. 22 (1), 9-17 (1993) be demonstrated
experimentally by means of the tests described hereinafter. The
tests can be carried out in analogy to those described by D. T.
Pals et al. in Hypertension Vol. 8, 1105-1112 (1986) or J. Boger et
al. in J. Med. Chem. 28, 1779-1790 (1985) or J. F. Dellaria et al.
in J. Med. Chem. 30, 2137-2144 (1987) or T. Kokubu et al. in
Biochem. Biophys. Res. Commun. 118, 929-933 (1984):
In Vitro Test with Pure Human Renin
The test is carried out in Eppendorf test tubes. The incubation
mixture consists of (1) 100 .mu.l of human renin in buffer A (0.1 M
sodium phosphate solution, pH 7.4, containing 0.1% bovine serum
albumin, 0.1% sodium azide and 1 mM ethylenediaminetetraacetic
acid), sufficient for a renin activity of 2-3 ng of angiotensin
I/ml/hr.; (2) 145 .mu.l of buffer A: (3) 30 .mu.l of 10 mM human
tetradecapeptide renin substrate (hTD) in 10 mM hydrochloric acid:
(4) 15 .mu.l of dimethyl sulphoxide with or without inhibitor and
(5) 10 .mu.l of a 0.03 molar solution of hydroxyquinoline sulphate
in water.
The samples are incubated for three hours at 37.degree. C. and,
respectively, 4.degree. C. in triplicate. 2.times.100 .mu.l samples
per test tube are used in order to measure the production of
angiotensin I via RIA (standard radioimmunoassay; clinical assay
solid phase kit). Cross reactivities of the antibody used in the
RIA are: angiotensin I 100%; angiotensin II 0.0013%; hTD
(angiotensin I-Val-Ile-His-Ser-OH) 0.09%. The production of
angiotensin I is determined by the difference between the test at
37.degree. C. and that at 4.degree. C.
The Following Controls are Carried Out
(a) Incubation of hTD samples without renin and without inhibitor
at 37.degree. C. and 4.degree. C. The difference between these two
values gives the base value of the angiotensin I production.
(b) Incubation of hTD samples with renin, but without inhibitor at
37.degree. C. and 4.degree. C. The difference between these values
gives the maximum value of the angiotensin I production.
In each sample the base value of the angiotensin I production is
subtracted from the angiotensin I production which is determined.
The difference between the maximum value and the base value gives
the value of the maximum substrate hydrolysis (=100%) by renin.
The results are given as IC.sub.50 values which denote the
concentration of the inhibitor at which the enzymatic activity is
inhibited by 50%. The IC.sub.50 values are determined from a linear
regression curve from a logit-log plot.
The results obtained in this test are compiled in the following
Table:
TABLE Compound IC.sub.50 values in nMol/l A 0.06 B 0.03 C 0.08 D
0.02 E 0.07 A = (R)-1-methoxy-3-[(3S, 4R,
5R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-methoxy-naphthalen
-2-ylmethoxy)-piperidin-3-yloxy]-propan-2-ol; B = (R)-1-[(3S, 4R,
5R)-4-[4-[3-(2-methoxy-benzloxy)-propoxy]-phenyl]-5-(4-methoxy-naphthalen-
2-ylmethoxy)-piperidin-3-yloxy]-3-(2-methoxy-ethoxy)-propan-2-ol; C
= (R)-3-[(3S, 4R,
5R)-5-(4-methoxy-naphthalen-2-ylmethoxy)-4-[4-[3-(2-nitro-phenoxy)-propoxy
]-phenyl]-piperidin-3-yloxy]-propane-1,2-diol; D = (3S, 4R,
5R)-[4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-methoxy-naphthale
n-2-ylmethoxy)-piperidin-3-yl]-methanol; and E = (3S, 4R,
5R)-3-imidazol-1-ylmethyl-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5
-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine dihydrochloride.
It will be appreciated that the compounds of general formula (I) in
this invention may be derivatised at functional groups to provide
prodrug derivatives which are capable of conversion back to the
parent compounds in vivo. Examples of such prodrugs include the
physiologically acceptable and metabolically labile ester
derivatives, such as methoxymethyl esters, methylthiomethyl esters
and pivaloyloxymethyl esters. Additionally, any physiologically
acceptable equivalents of the compounds of general formula (I),
similar to the metabolically labile esters, which are capable of
producing the parent compounds of general formula (I) in vivo, are
within the scope of this invention.
As mentioned earlier, medicaments containing a compound of formula
(I) are also an object of the present invention, as is a process
for the manufacture of such medicaments, which process comprises
bringing one or more compounds of formula (I) and, if desired, one
or more other therapeutically valuable substances into a galenical
administration form.
The pharmaceutical compositions may be administered orally, for
example in the form of tablets, coated tablets, dragees, hard or
soft gelatine capsules, solutions, emulsions or suspensions.
Administration can also be carried out rectally, for example using
suppositories; locally or percutaneously, for example using
ointments, creams, gels or solutions; or parenterally, e.g.
intravenously, intramuscularly, subcutaneously, intrathecally or
transdermally, using for example injectable solutions. Furthermore,
administration can be carried out sublingually or as
opthalmological preparations or as an aerosol, for example in the
form of a spray.
For the preparation of tablets, coated tablets, dragees or hard
gelatine capsules the compounds of the present invention may be
admixed with pharmaceutically inert, inorganic or organic
excipients. Examples of suitable excipients for tablets, dragees or
hard gelatine capsules include lactose, maize starch or derivatives
thereof, talc or stearic acid or salts thereof.
Suitable excipients for use with soft gelatine capsules include for
example vegetable oils, waxes, fats, semi-solid or liquid polyols
etc.; according to the nature of the active ingredients it may
however be the case that no excipient is needed at all for soft
gelatine capsules.
For the preparation of solutions and syrups, excipients which may
be used include for example water, polyols, saccharose, invert
sugar and glucose.
For injectable solutions, excipients which may be used include for
example water, alcohols, polyols, glycerine, and vegetable
oils.
For suppositories, and local or percutaneous application,
excipients which may be used include for example natural or
hardened oils, waxes, fats and semi-solid or liquid polyols.
The pharmaceutical compositions may also contain preserving agents,
solubilising agents, stabilising agents, wetting agents,
emulsifiers, sweeteners, colorants, odorants, salts for the
variation of osmotic pressure, buffers, coating agents or
antioxidants. As mentioned earlier, they may also contain other
therapeutically valuable agents.
It is a prerequisite that all adjuvants used in the manufacture of
the preparations are non-toxic.
Intravenous, intramuscular or oral administration is a preferred
form of use. The dosages in which the compounds of formula (I) are
administered in effective amounts depend on the nature of the
specific active ingredient, the age and the requirements of the
patient and the mode of application. In general, daily dosages of
about 1 mg-1000 mg, preferably 10 mg-300 mg, per day come into
consideration.
The following Examples shall illustrate preferred embodiments of
the present invention but are not intended to limit the scope of
the invention.
EXAMPLES
Example 1
(R)-1-methoxy-3-[(3S,4R,5R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-
5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-3-yloxy]-propan-2-ol)
(a) 50.0 g (129.7 mmol) of
(3S)-4-(4-benzyloxy-phenyl)-1-[(1R)-phenyl-ethyl]-1,2,3,6-tetrahydro-pyrid
in-3-ol were dissolved in 700 ml of N,N-dimethylformamide, treated
portionwise with 41.5 g (about 1040 mmol) of sodium hydride
dispersion in refined oil (55-65%) and the reaction mixture was
stirred under argon for 1 hour. Then the mixture was treated
portionwise with 153.1 g (519 mmol) of
(R)-(-)-2,2-dimethyl-4-(hydroxymethyl)-[1,3]dioxolane-p-toluenesulfonate
and stirred for two hours. Thereupon, the reaction mixture was
poured into 2 liter of ice-water and extracted three times with 750
ml of ether. The combined ether phases were subsequently washed
with water, dried over magnesium sulphate and evaporated on a
rotary evaporator at a maximum 40.degree. C. The residue which was
thereby obtained was chromatographed on silica gel with
methylenechloride/ethyl acetate (95/5). There were thus obtained
64.8 g (115 mmol), 88.7%,
(3S)-4-(4-benzyloxy-phenyl)-3-[(4S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy
]-1-[(R)-1-phenyl-ethyl]-1,2,3,6-tetrahydro-pyridine as light
yellow solid; MS: 500 (M+H).sup.+.
(b) 29.4 g (58.8 mmol) of
(3S)-4-(4-benzyloxy-phenyl)-3-[(4S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy
]-1-[(R)-1-phenyl-ethyl]-1,2,3,6-tetrahydro-pyridine were dissolved
in 175 ml of 1,2-dimethoxyethane, cooled to 5.degree. C., treated
with 235.4 ml of a 1.0 M solution of borane-tetrahydrofuran complex
in tetrahydrofuran and stirred at room temperature for 5.5 hours.
Then, the reaction mixture was again cooled to 5.degree. C.,
treated slowly with 110 ml of water followed by 44.3 g (282 mmol)
of sodium percarbonate. Subsequently, the reaction mixture was
stirred at 50.degree. C. for 17 hours. After cooling to room
temperature the reaction solution was poured into 1.6 liters of
water and extracted twice with 600 ml of dichloromethane each time.
The combined dichloromethane phases were washed with water, dried
over magnesium sulphate and evaporated on a rotary evaporator at a
maximum 40.degree. C.
The residue which was thereby obtained was chromatographed on
silica gel with dichloromethane/ethyl acetate (8/2). There were
thus obtained 23.1 g (44.6 mmol), 75.8%,
(3R,4R,5S)-4-(4-benzyloxy-phenyl)-5-[(4S)-2,2-dimethyl-[1,3]dioxolan-4-ylm
ethoxyl]1-[(R)-1-phenyl-ethyl]-piperidin-3-ol as colorless solid;
MS: 518 (M+H).sup.+.
(c) 19.2 g (37.1 mmol)
(3R,4R,5S)-4-(4-benzyloxy-phenyl)-5-[(4S)-2,2-dimethyl-[1,3]dioxolan-4-ylm
ethoxy]-1-[(R)-1-phenyl-ethyl]-piperidin-3-ol dissolved in 200 ml
methanol were hydrogenated in the presence of 3.84 g of palladium
catalyst (10% on charcoal) for 23 hours. The reaction mixture was
then filtered and evaporated yielding 12 g crude
(3R,4R,5S)-5-[(4S)-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-4-(4-hydroxy-p
henyl)-piperidin-3-ol as colorless solid; MS: 324.3
(M+H).sup.+.
(d) 26.4 g (81.6 mmol) crude
(3R,4R,5S)-5-[(4S)-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-4-(4-hydroxy-p
henyl)-piperidin-3-ol were dissolved in 160 ml dioxane/50 ml water
and treated with 20 g (90 mmol) di-tert.-butyldicarbonate and 14.4
g (171 mmol) sodium hydrogencarbonate. The reaction mixture was
then stirred for 1 hour. 150 ml 2N NaOH were then added and the
mixture again stirred for an additional 30 minutes. It was then
acidified to pH 7 with 130 ml 2N HCl solution. Thereafter, the
reaction mixture was diluted with 500 ml of water extracted 3 times
with 500 ml of dichloromethane, the organic phases were washed
twice with distilled water, then dried over magnesium sulphate,
filtered and concentrated in a water-jet vacuum. The thus-obtained
crude product was chromatographed on silica gel with
dichloromethane/ethyl acetate (7/3). There were thus obtained 29.4
g (69.4 mmol), 85%
(3S,4R,5R)-3-[(4S)-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-5-hydroxy-4-(4
-hydroxy-phenyl)-piperidine-1-carboxylic acid tert-butyl ester as
light brown oil; MS: 424.3 (M+H).sup.+.
(e) A solution of 18 g (42.5 mmol) of
(3S,4R,5R)-3-[(4S)-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-5-hydroxy-4-(4
-hydroxy-phenyl)-piperidine-1-carboxylic acid tert-butyl ester in
120 ml of N,N-dimethylformamide was treated in succession with 13.6
g (63.8 mmol) of 1-(3-chloro-propoxymethyl)-2-methoxy-benzene (WO
97/09311) and 8.8 g (63.8 mmol) of potassium carbonate. This
mixture was stirred at 120.degree. C. for 16 hours. Subsequently,
it was filtered, concentrated to a few milliliters, poured into 800
ml of an ice/water mixture and extracted three times with 300 ml of
ether each time. The combined organic phases were washed once with
a small amount of water, dried over magnesium sulphate, evaporated
under reduced pressure and dried in a high vacuum. The
thus-obtained crude product was separated on silica gel using a
mixture of dichloromethane/ethyl acetate (7/3) as the eluent and
yielded 24.5 g (40.6 mmol), 95.6%,
(3S,4R,5R)-3-[(4S)-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-5-hydroxy-4-[4
-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic
acid tert-butyl ester as slightly yellow oil; MS: 602.3
(M+H).sup.+.
(f) 24.5 g (40.6 mmol) of
(3S,4R,5R)-3-[(4S)-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-5-hydroxy-4-[4
-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic
acid tert-butyl ester and 12.6 g (60.9 mmol) of
3-chloromethyl-1-methoxy-naphthalene [example 1) [.alpha.] were
dissolved in 150 ml of N,N-dimethylformamide under argon and then
6.50 g (162 mmol) of sodium hydride dispersion (55% in mineral oil)
was added. Subsequently, the mixture was stirred at room
temperature for 1.5 hours. The reaction mixture was poured into 600
ml of ice-water, the product was extracted 3 times with 300 ml of
ether, the organic phases were washed twice with distilled water,
then dried over magnesium sulphate, filtered and concentrated in a
water-jet vacuum. The thus-obtained crude product was
chromatographed on silica gel using a mixture of
dichloromethane/ethyl acetate (95/5) as the eluent and yielded 28.5
g (36.9 mmol), 90.9%,
(3S,4R,5R)-3-[(4S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-4-[4-[3-(2-meth
oxy-benzyloxy)-propoxy]-phenyl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperi
dine-1-carboxylic acid tert-butyl ester as colorless oil; MS: 772.5
(M+H).sup.+.
(g) 28.5 g (36.9 mmol)
of(3S,4R,5R)-3-[(4S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-4-[4-[3-(2-me
thoxy-benzyloxy)-propoxy]-phenyl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-pipe
ridine-1-carboxylic acid tert-butyl ester were dissolved in 150 ml
of abs. methanol at 0.degree. C., then 118 ml (236 mmol) of
hydrochloric acid in methanol (2.0 molar) were added dropwise at
5.degree. C. max. and thereafter the mixture was warmed to room
temperature. After 22 hours the reaction mixture was poured into
ice-cold sodium hydrogen carbonate solution (1 l , 60 g sodium
hydrogencarbonate) and the product was extracted three times with
500 ml dichloromethane, the organic phases were washed with
distilled water, then dried over magnesium sulphate, filtered and
concentrated in a water-jet vacuum. There were thus obtained 20.9 g
(33.1 mmol), 90%,
(R)-3-[(3S,4R,5R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-meth
oxy-naphthalen-2-ylmethoxy)-piperidin-3-yloxy]-propane-1,2-diol as
colorless oil; MS: 632.4 (M+H).sup.+.
(h) 20.9 g (33.1 mmol) of
(R)-3-[(3S,4R,5R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-meth
oxy-naphthalen-2-ylmethoxy)-piperidin-3-yloxy]-propane-1,2-diol
were dissolved in 357 ml dioxane/178 ml water and treated with 7.6
g (35.0 mmol) di-tert.-butyldicarbonate and 6.3 g (74.7 mmol)
sodium hydrogencarbonate. The reaction mixture was then stirred for
1 hour. 150 ml 2 N NaOH were then added and the mixture again
stirred for an additional 30 minutes. It was then acidified to pH 7
with 130 ml 2N HCl solution. Thereafter, the reaction mixture was
diluted with 600 ml of water extracted 3 times with 500 ml of
dichloromethane, the organic phases were washed twice with
distilled water, then dried over magnesium sulphate, filtered and
concentrated in a water-jet vacuum. The thus-obtained crude product
was chromatographed on silica gel with dichloromethane/methanol
(10/0 to 9/1). There were thus obtained 23.7 g (32.3 mmol), 97.6%,
(3S,4R,5R)-3-[(2R)-2,3-dihydroxy-propoxy]-4-[4-[3-(2-methoxy-benyloxy)-pro
poxy]-phenyl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic
acid tert-butyl ester as colorless oil; MS:732.5 (M+H).sup.+.
(i) 23.65 g (32.3 mmol) of
(3S,4R,5R)-3-[(2R)-2,3-dihydroxy-propoxy]-4[4-3-(2-methoxy-benzyloxy)-prop
oxy]-phenyl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic
acid tert-butyl ester were dissolved in 118 ml pyridine and treated
while stirring rapidly with 31.1 g (162 mmol)
toluol-4-sulfochlorid. After 15 minutes stirring at room
temperature, 140 ml of water and 140 ml of tetrahydrofuran were
added and stirring continued for additional 40 minutes. Thereafter,
the reaction mixture was diluted with 11 of water extracted 3 times
with 500 ml of dichloromethane, the organic phases were washed
three times with 400 ml 1N HCl solution and twice with distilled
water, then dried over magnesium sulphate, filtered and
concentrated in a water-jet vacuum. The thus-obtained crude product
was chromatographed on silica gel with dichloromethane/ethyl
acetate (9/1) giving 21.2 g of a mixture of the primary and the
secondary tosylate. Separation on an HPLC silica gel column using
hexane/isopropanol as eluent yielded 18.5 g (20.9 mmol), 64.
6%(3S,4R,5R)-3-[(2S)-2-hydroxy-3-(toluene-4-sulfonyloxy)-propoxy]-4-[4-[3-
(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-methoxy-naphthalen-2-ylmethoxy)
-piperidine-1-carboxylic acid tert-butyl ester as colorless oil
[MS: 886.4 (M+H).sup.+ ] and 1.3 g (1.47 mmol), 4.5%
(3S,4R,5R)-3-[(2R)-3-hydroxy-2-(toluene-4-sulfonyloxy)-propoxy]-4-[4-[3-(2
-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-p
iperidine-1-carboxylic acid tert-butyl ester as colorless oil; MS:
886.4 (M+H).sup.+.
(j) 18.5 g (20.9 mmol) of
(3S,4R,5R)-3-[(2S)-2-hydroxy-3-(toluene-4-sulfonyloxy)-propoxy]-[4-[3-(2-m
ethoxy-benzyloxy)-propoxy]-phenyl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-pip
eridine-1-carboxylic acid tert-butyl ester were dissolved in 530 ml
dimethylsulfoxid and treated while stirring at room temperature
with 90.7 ml (454 mmol) 5M sodium hydroxide solution. The reaction
mixture was then stirred for 1 hour , diluted with 800 ml of water
and extracted twice with 400 ml of ether. The organic phases were
washed twice with distilled water, then dried over magnesium
sulphate, filtered and concentrated in a water-jet vacuum. There
were thus obtained 14.7 g (20.6 mmol), 99%
(3R,4R,5S)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-3-(4-methoxy-nap
hthalen-2-ylmethoxy)-5-[(2R)-oxiranylmethoxy]-piperidine-1-carboxylic
acid tert-butyl ester as colorless oil; MS: 714.3 (M+H).sup.+.
(k) 14.7 g (20.6 mmol) of
(3R,4R,5S)-4-[4-[3-(2-methoxy-benzyloxy)-propoxyl]-phenyl]-3-(4-methoxy-na
phthalen
-2-ylmethoxy)-5-[(2R)-oxiranylmethoxy]-piperidine-1-carboxylic acid
tert-butyl ester were dissolved in 98 ml N,N-dimethylformamide and
treated at room temperature while stirring with 21.9 ml (118 mmol)
5.4M sodium methylate solution in methanol. The reaction mixture
was then stirred for 16 hours, diluted with 400 ml of water and
extracted twice with 300 ml of ether. The organic phases were
washed twice with distilled water, then dried over magnesium
sulphate, filtered and concentrated in a water-jet vacuum.
There were thus obtained 15.3 g (20.5 mmol), 99.5%
(3S,4R,5R)-3-[(2R)-2-hydroxy-3-methoxy-propoxy]-4-[4-[3-(2-methoxy-benzylo
xy)-propoxy]-phenyl]-5-(4-methoxy-naphthalen-2-ylmethoxy
)-piperidine-1-carboxylic acid tert-butyl ester as colorless oil;
MS: 746.4 (M+H).sup.+.
(l) 15.3 g (20.5 mmol) of
(3S,4R,5R)-3-[(2R)-2-hydroxy-3-methoxy-propoxy]-4-[4-[3-(2-methoxy-benzylo
xy)-propoxy]-phenyl]5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carbo
xylic acid tert-butyl ester were dissolved in 70 ml of abs.
methanol at 0.degree. C., then 118 ml (236 mmol) of hydrochloric
acid in methanol (2.0 molar) were added dropwise at 5.degree. C.
max. and thereafter the mixture was warmed to room temperature.
After 22 hours the reaction mixture was poured into ice-cold sodium
hydrogen carbon ate solution (1 l , 60 g sodium hydrogen carbonate)
and the product was extracted three times with 500 ml
dichloromethane, the organic phases were washed with distilled
water, then dried over magnesium sulphate, filtered and
concentrated in a water-jet vacuum. The thus-obtained crude product
was chromatographed on silica gel with dichloromethane methanol
(95/5). There were thus obtained 9.3 g (14.4 mmol), 70.2%,
(R)-1-methoxy-3-[(3S,4R,5R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]
-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-3-yloxy]-propan-2-ol
as colorless oil; MS: 646.3 (M+H).sup.+.
Preparation of 3-chloromethyl-1-methoxy-naphthalene
(a) 15.0 g (79.7 mmol) of (4-methoxy-naphthalen-2-yl)-methanol
[Chem. Pharm. Bull. 19(6), 1245-1256 (1971)] were dissolved in 100
ml of dichloromethane, the solution treated with 20 ml of
triethylamine, cooled to -5.degree. C. and treated slowly with 9.3
ml (119.5 mmol) methanesulfonyl chloride. Then, the reaction
mixture was stirred at room temperature for 23 hours, concentrated
in a water-jet vacuum, redissolved in 80 ml of tetrahydrofuran,
treated with 11.25 g of sodium hydrogen carbonate and stirred for
another 2 hours. The suspension was then diluted with 500 ml of
water and extracted three times with 300 ml of ethyl acetate, the
organic phases were washed once with distilled water, then dried
over magnesium sulphate, filtered and concentrated in a water-jet
vacuum. The thus-obtained crude product was chromatographed on
silica gel with pentane/dichloromethane (4/1). There were thus
obtained 11.9 g (57.5 mmol), 72.5%
3-chloromethyl-1-methoxy-naphthalene as a colorless solid; MS: 206
(M).sup.+.
Example 2
(S)-1-methoxy-3-[(3S,4R,5R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-
5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-3-yloxy]-propan-2-ol
(a) In analogy to the procedure described in example 1 (j) the
(3S,4R,5R)-3-[(2R)-3-hydroxy-2-(toluene-4-sulfonyloxy)-propoxy]-4-[4-[3-(2
-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-p
iperidine-1-carboxylic acid tert-butyl ester [example 1) (i)] was
treated with sodium hydroxide in dimethylsulfoxide to yield the
(3R,4R,5S)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-3-(4-methoxy-ylm
ethoxy)-5-[(2S)-oxiranylmethoxy]-piperidine-1-carboxylic acid
tert-butyl ester as colorless oil; MS: 714.3 (M+H).sup.+.
(b) In analogy to the procedure described in example 1 (k) the
(3R,4R,5S)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-3-(4-methoxy-nap
hthalen-2-ylmethoxy)-5-[(2S)-oxiranylmethoxy]-piperidine-1-carboxylic
acid tert-butyl ester was treated with sodium methylate in
N,N-dimethylformamide to yield the
(3S,4R,5R)-3-[(2S)-2-hydroxy-3-methoxy-propoxy]-4-[4-[3-(2-methoxy-benzylo
xy)-propoxy]-phenyl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carb
oxylic acid tert-butyl ester as colorless oil; MS: 746.4
(M+H).sup.+.
(c) In analogy to the procedure described in example 1) (l) the
(3S,4R,5R)-3-[(2S)-2-hydroxy-3-methoxy-propoxy]-4-[4-[3-(2-methoxy-benzylo
xy)-propoxy]-phenyl]-5(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carbo
xylic acid tert-butyl ester was deprotected with HCl in methanol to
yield the
(2S)-1-methoxy-3-[(3S,4R,5R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl
]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-3-yloxy]-propan-2-ol
as colorless oil; MS: 646.3 (M+H).sup.+.
Example 3
(R)-1-[(3S,4R,5R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-metho
xy-naphthalen-2-ylmethoxy)-piperidin-3-yloxy]-3-(2-methoxy-ethoxy)-propan-2
-ol
(a) In analogy to the procedure described in example 1 (k) the
(3R,4R,5S)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-3-(4-methoxy-nap
hthalen-2-ylmethoxy)-5-[(2R)-oxiranylmethoxy]-piperidine-1-carboxylic
acid tert-butyl ester was treated with sodium 2-methoxy-ethylate
(prepared from 2-methoxy-ethanol and sodium hydride) to give the
(3S,4R,5R)-3-[(2R)-2-hydroxy-3-(2-methoxy-ethoxy)-propoxy]-4-[4-[3-(2-meth
oxy-benzyloxy)-propoxy]-phenyl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperi
dine-1-carboxylic acid tert-butyl ester as colorless oil; MS: 790.4
(M+H).sup.+.
(b) In analogy to the procedure described in example 1) (l) the
(3S,4R,5R)-3-[(2R)-2-hydroxy-3-(2-methoxy-ethoxy)-propoxy]-4-[4-[3-(2-meth
oxy-benzyloxy)-propoxy]-phenyl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperi
dine-1-carboxylic acid tert-butyl ester was deprotected with HCl in
methanol to yield the
(R)-1-[(3S,4R,5R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-meth
oxy-naphthalen-2-ylmethoxy)-piperidin-3-yloxy]-3-(2-methoxy-ethoxy)-propan-
2-ol as colorless oil; MS: 690.3 (M+H).sup.+.
Example 4
(R)-1-[(3S,4R,5R)-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-methoxy
-naphthalen-2-ylmethoxy)-piperidin-3-yloxy]-3-methylamino-propan-2-ol
(a) 50 mg (0.070 mmol)
(3R,4R,5S)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-3-(4-methoxy-nap
hthalen-2-ylmethoxy)-5-[(2R)-oxiranylmethoxy]-piperidine-1-carboxylic
acid tert-butyl ester were dissolved in 0.45 ml (3.6 mmol) 8.03 M
solution of methylamine in ethanol. The reaction mixture was
stirred for 16 hours at 70.degree. C. in a closed wessel. The
reaction mixture was then concentrated in a water-jet vacuum and
the thus-obtained crude product was chromatographed on silica gel
with dichloromethane/methanol/sat. aq. ammonia (95/5/0.1). There
were thus obtained 52.2 mg (0.049 mmol), 70%
(3S,4R,5R)-3-[(2R)-2-hydroxy-3-methylamino-propoxy)-4-[4-[3-(2-methoxy-ben
zyloxy)-propoxy]-phenyl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-
carboxylic acid tert-butyl ester as colorless oil; MS: 745.5
(M+H).sup.+.
(b) In analogy to the procedure described in example 1) (l) the
(3S,4R,5R)-3-[(2R)-2-hydroxy-3-methylamino-propoxy)-4-[4-[3-(2-methoxy-ben
zyloxy)-propoxy]-phenyl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-
carboxylic acid tert-butyl ester was deprotected with HCl in
methanol to yield the
(R)-1-[(3S,4R,5R)-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-methox
y-naphthalen-2-ylmethoxy)-piperidin-3-yloxy]-3-methylamino-propan-2-ol
as colorless oil; MS: 645.3 (M+H).sup.+.
Example 5
2-[3-[4-[(3S,4R,5R)-3-[(2R)-2,3-dihydroxy-propoxy]-5-(4-methoxy-naphthalen-
2-ylmethoxy)-piperidin-4-yl]-phenoxy]-propoxy]-benzonitrile
(a) 50.0 g (416 mmol) of 2-hydroxy-benzonitril and 101 g (499 mmol)
of 1,3-dibromo-propane were dissolved in 450 ml of 2-butanone, 138
g (997 mmol) of potassium carbonate were then added and the
reaction mixture stirred under reflux for 2 hours. After cooling to
room temperature, the mixture was filtered and the filtrate
concentrated in a water-jet vacuum. Thereafter 250 ml of ice-water
were added and the product was extracted three times with 200 ml
dichloromethane, the organic phases were washed with 10% of
potassium carbonate solution followed by distilled water, then
dried over magnesium sulphate, filtered and concentrated in a
water-jet vacuum. The thus-obtained crude product crystallized, the
crystals were filtered off and washed with hexane. There were thus
obtained 44.8 g (187 mmol), 44.9% 2-(3-bromo-propoxy)-benzonitrile
as colorless solid; MS: 239, 241 (M).sup.+.
(b) In analogy to the procedure described in example 1) (e) the
(3S,4R,5R)-3-[(4S)-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-5-hydroxy-4-(4
-hydroxy-phenyl)-piperidine-1-carboxylic acid tert-butyl ester was
treated with the 2-(3-bromo-propoxy)-benzonitrile to yield the
(3S,4R,5R)-4-[4-[3-(2-cyano-phenoxy)-propoxy]-phenyl]-3-[(4S)-2,2-dimethyl
-[1,3]dioxolan-4-ylmethoxy]-5-hydroxy-piperidine-1-carboxylic acid
tert-butyl ester as colorless oil; MS: 583 (M+H).sup.+.
(c) In analogy to the procedure described in example 1) (f) the
(3S,4R,5R)-4-[4-[3-(2-cyano-phenoxy)-propoxy]-phenyl]-3-[(4S)-2,2-dimethyl
-[1,3]dioxolan-4-ylmethoxy]-5-hydroxy-piperidine-1-carboxylic acid
tert-butyl ester was reacted with
3-chloromethyl-1-methoxy-naphthalene [example 1 (.alpha.)] to yield
the
(3S,4R,5R)-4-[4-[3-(2-cyano-phenoxy-propoxy]-phenyl]-3-[(4S)-2,2-dimethyl-
[1,3]dioxolan-4-ylmethoxy]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-
1-carboxylic acid tert-butyl ester as colorless oil; MS: 753
(M+H).sup.+.
(d) In analogy to the procedure described in example 1) (g) the
(3S,4R,5R)-4-[4-[3-(2-cyano-phenoxy)-propoxy]-phenyl]-3-[(4S)-2,2-dimethyl
-[1,3]dioxolan-4-ylmethoxy]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine
-1-carboxylic acid tert-butyl ester was deprotected with HCl in
methanol to yield the
2-[3-[4-[(3S,4R,5R)-3-[(2R)-2,3-dihydroxy-propoxy]-5-(4-methoxy-naphthalen
-2-ylmethoxy)-piperidin-4-yl]-phenoxy]-propoxy]-benzonitrile as
white foam; MS: 613 (M+H).sup.+.
Example 6
2-[3-[4-[(3S,4R,5R)-3-[(2R)-2-hydroxy-3-methoxy-propoxy]-5-(4-methoxy-napht
halen-2-ylmethoxy)-piperidin-4-yl]-phenoxy]-propoxy]-benzonitrile
(a) In analogy to the procedure described in example 1 (h) the
2-[3-[4-[(3S,4R,5R)-3-[(2R)-2,3-dihydroxy-propoxy]-5-(4-methoxy-naphthalen
-2-ylmethoxy)-piperidin-4-yl]-phenoxy]-propoxy]-benzonitrile was
treated with di-tert.-butyldicarbonate to yield the
(3S,4R,5R)-4-[4-[3-(2-cyano-phenoxy)-propoxy]-phenyl]-3-[(2R)-2,3-dihydrox
y-propoxyl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic
acid tert-butyl ester as colorless oil; MS: 713 (M+H).sup.+.
(b) In analogy to the procedure described in example 1) (i) the
(3S,4R,5R)-4-[4-[3-(2-cyano-phenoxy)-propoxy]-phenyl]-3-[(2R)-2,3-dihydrox
y-propoxy]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic
acid tert-butyl ester was treated with toluol-4-sulfochlorid to
yield the
(3S,4R,5R)-4-[4-[3-(2-cyano-phenoxy)-propoxy]-phenyl]-3-[(2S)-2-hydroxy-3-
(toluene-4-sulfonyloxy)-propoxy]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piper
idine-1-carboxylic acid tert-butyl ester as colorless foam; MS: 868
(M+H.sup.+).
(c) In analogy to the procedure described in example 1) (j) the
(3S,4R,5R)-4-[4-[3-(2-cyano-phenoxy)-propoxy]-phenyl]-3-[(2S)-2-hydroxy-3-
(toluene-4-sulfonyloxy)-propoxy]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piper
idine-1-carboxylic acid tert-butyl ester was treated with sodium
hydroxide solution in dimethylsulfoxide to yield the
(3R,4R,5S)-4-[4-[3-(2-cyano-phenoxy)-propoxy]-phenyl]-3-(4-methoxy-naphtha
len-2-ylmethoxy)-5-[(2R)-oxiranylmethoxy]-piperidine-1-carboxylic
acid tert-butyl ester as colorless oil; MS: 695 (M+H).sup.+.
(d) In analogy to the procedure described in example 1 (k) the
(3R,4R,5S)-4-[4-[3-(2-cyano-phenoxy)-propoxy]-phenyl]-3-(4-methoxy-naphtha
len-2-ylmethoxy)-5-[(2R)-oxiranylmethoxy]-piperidine-1-carboxylic
acid tert-butyl ester was treated with sodium methoxide in
N,N-dimethylformamide to yield the
(3S,4R,5R)-4-[4-[3-(2-cyano-phenoxy)-propoxy]-phenyl]-3-[(2R)-2-hydroxy-3-
methoxy-propoxy]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxyl
ic acid tert-butyl ester as colorless foam; MS: 727
(M+H.sup.+).
(e) In analogy to the procedure described in example 1 (l) the
(3S,4R,5R)-4-[4-[3-(2-cyano-phenoxy)-propoxy]-phenyl]-3-[(2R)-2-hydroxy-3-
methoxy-propoxy]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxyl
ic acid tert-butyl ester was deprotected with HCl in methanol to
yield the
2-[3-[4-[(3S,4R,5R)-3-[(2R)-2-hydroxy-3-methoxy-propoxy]-5-(4-methoxy-naph
thalen-2-ylmethoxy)-piperidin-4-yl]-phenoxy]-propoxy]-benzonitrile
as colorless oil; MS: 627 (M+H).sup.+.
Example 7
2-[3-[4-[(3S,4R,5R)-3-[(2R)-2-hydroxy-3-(2-methoxy-ethoxy)-propoxy]5-(4-met
hoxy-naphthalen-2-ylmethoxy)-piperidin-4-yl]-phenoxy]-propoxy]-benzonitrile
(a) In analogy to the procedure described in example 1 (k) the
(3R,4R,5S)-4-[4-[3-(2-cyano-phenoxy)-propoxy]-phenyl]-3-(4-methoxy-naphtha
len-2-ylmethoxy)-5-[(2R)-oxiranylmethoxy]-piperidine-1-carboxylic
acid tert-butyl ester was treated with sodium 2-methoxy-ethylate
(prepared from 2-methoxy-ethanol and sodium hydride) to give the
(3S,4R,5R)-4-[4-[3-(2-cyano-phenoxy)-propoxy]-phenyl]-3-[(2R)-2-hydroxy-3-
(2-methoxy-ethoxy)-propoxy]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine
-1-carboxylic acid tert-butyl ester as colorless oil; MS: 771
(M+H).sup.+.
(b) In analogy to the procedure described in example 1 (l) the
(3S,4R,5R)-4-[4-[3-(2-cyano-phenoxy)-propoxy]-phenyl]-3-[(2R)-2-hydroxy-3-
(2-methoxy-ethoxy)-propoxy]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine
-1-carboxylic acid tert-butyl ester was deprotected with HCl in
methanol to yield the
2-[3-[4-[(3S,4R,5R)-3-[(2R)-2-hydroxy-3-(2-methoxy-ethoxy)-propoxy]-5-(4-m
ethoxy-naphthalen-2-ylmethoxy)-piperidin-4-yl]-phenoxy]-propoxy]-benzonitri
le as colorless foam; MS: 671 (M+H).sup.+.
Example 8
(R)-3-[(3S,4R,5R)-5-(4-methoxy-naphthalen-2-ylmethoxy)-4-[4-[3-(2-nitro-phe
noxy)-propoxy]-phenyl]-piperidin-3-yloxy]-propane-1,2-diol
(a) In analogy to the procedure described in example 5) (a)
2-nitrophenol was treated with sodium carbonate followed by
1,3-dibromo-propane in N,N-dimethylformamide to yield the
1-(3-bromo-propoxy)-2-nitro-benzene as slightly green solid; MS:
259, 261 (M).sup.+.
(b) In analogy to the procedure described in example 1) (e) the
(3S,4R,5R)-3-[(4S)-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-5-hydroxy-4-(4
-hydroxy-phenyl)-piperidine-1-carboxylic acid tert-butyl ester was
treated with the 1-(3-bromo-propoxy)-2-nitro-benzene to yield the
(3S,4R,5R)-3-[(4S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-5-hydroxy-4-[4-
[3-(2-nitro-phenoxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid
tert-butyl ester as colorless oil; MS: 603 (M+H).sup.+.
(c) In analogy to the procedure described in example 1) (f) the
(3S,4R,5R)-3-[(4S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-5-hydroxy-4-[4-
[3-(2-nitro-phenoxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid
tert-butyl ester was reacted with
3-chloromethyl-1-methoxy-naphthalene [example 1) (a)] to yield the
(3S,4R,5R)-3-[(4S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-5-(4-methoxy-na
phthalen-2-ylmethoxy)-4-[4-[3-(2-nitro-phenoxy)-propoxy]-phenyl]-piperidine
-1-carboxylic acid tert-butyl ester as colorless oil; MS: 773
(M+H).sup.+.
(d) In analogy to the procedure described in example 1) (g) the
(3S,4R,5R)-3-[(4S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-5-(4-methoxy-na
phthalen-2-ylmethoxy)-4-[4-[3-(2-nitro-phenoxy)-propoxy]-phenyl]-piperidine
-1-carboxylic acid tert-butyl ester was deprotected with HCl in
methanol to yield the
(R)-3-[(3S,4R,5R)-5-(4-methoxy-naphthalen-2-ylmethoxy)-4-[4-[3-(2-nitro-ph
enoxy)-propoxy]-phenyl]-piperidin-3-yloxy]-propane-1,2-diol as
light yellow solid; MS: 633 (M+H).sup.+.
Example 9
(R)-1-[(3S,4R,5R)-5-(4-methoxy-naphthalen-2-ylmethoxy)-4-[4-[3-(2-nitro-phe
noxy)-propoxy]-phenyl]-piperidin-3-yloxy]-3-[1,2,4]triazol-1-yl-propan-2-ol
(a) In analogy to the procedure described in example 1 (h) the
(R)-3-[(3S,4R,5R)-5-(4-methoxy-naphthalen-2-ylmethoxy)-4-[4-[3-(2-nitro-ph
enoxy)-propoxy]-phenyl]-piperidin-3-yloxy]-propane-1,2-diol was
treated with di-tert.-butyldicarbonate to yield the
(3S,4R,5R)-3-[(2R)-2,3-dihydroxy-propoxy]-5-(4-methoxy-naphthalen-2-ylmeth
oxy)4-[4-[3-(2-nitro-phenoxy)-propoxy]-phenyl]-piperidine-1-carboxylic
acid tert-butyl ester as light yellow foam; MS: 733
(M+H).sup.+.
(b) In analogy to the procedure described in example 1 (i)
(3S,4R,5R)-3-[(2R)-2,3-dihydroxy-propoxy]-5-(4-methoxy-naphthalen-2-ylmeth
oxy)-4-[4-[3-(2-nitro-phenoxy)-propoxy]-phenyl]-piperidine-1-carboxylic
acid tert-butyl ester was treated with toluol-4-sulfochlorid to
yield the
(3S,4R,5R)-3-[(2S)-2-hydroxy-3-(toluene-4-sulfonyloxy)-propoxy]-5-(4-metho
xy-naphthalen-2-ylmethoxy)-4-[4-[3-(2-nitro-phenoxy)-propoxy]-phenyl]-piper
idine-1-carboxylic acid tert-butyl ester as light yellow foam; MS:
887 (M).sup.+.
(c) In analogy to the procedure described in example 1) (j) the
(3S,4R,5R)-3-[(2S)-2-hydroxy-3-(toluene-4-sulfonyloxy)-propoxy]-5-(4-metho
xy-naphthalen-2-ylmethoxy)-4-[4-[3-(2-nitro-phenoxy)-propoxy]-phenyl]-piper
idine-1-carboxylic acid tert-butyl ester was treated with sodium
hydroxide solution in dimethylsulfoxide to yield the
(3R,4R,5S)-3-(4-methoxy-naphthalen-2-ylmethoxy)-4-[4-[3-(2-nitro-phenoxy)-
propoxy]-phenyl]-5-[(2R)-oxiranylmethoxy]-piperidine-1-carboxylic
acid tert-butyl ester as light yellow foam; MS: 715
(M+H).sup.+.
(d) In analogy to the procedure described in example 1) (k) the
(3R,4R,5S)-3-(4-methoxy-naphthalen-2-ylmethoxy)-4-[4-[3-(2-nitro-phenoxy)-
propoxy]-phenyl]-5-[(2R)-oxiranylmethoxy]-piperidine-1-carboxylic
acid tert-butyl ester was treated with [1,2,4]triazol and sodium
hydride in N,N-dimethylformamide to yield the
(3S,4R,5R)-3-[(2R)-2-hydroxy-3-[1,2,4]triazol-1-yl-propoxy]-5-(4-methoxy-n
aphthalen-2-ylmethoxy)-4-[4-[3-(2-nitro-phenoxy)-propoxy]-phenyl]-piperidin
e-1-carboxylic acid tert-butyl ester as colorless oil; MS: 784
(M+H).sup.+.
(e) In analogy to the procedure described in example 1) (1) the
(3S,4R,5R)-3-[(2R)-2-hydroxy-3-[1,2,4]triazol-1-yl-propoxy]-5-(4-methoxy-n
aphthalen-2-ylmethoxy)-4-[4-[3-(2-nitro-phenoxy)-propoxy]-phenyl]-piperidin
e-1-carboxylic acid tert-butyl ester was deprotected with HCl in
methanol to yield the
(R)-1-[(3S,4R,5R)-5-(4-methoxy-naphthalen-2-ylmethoxy)-4-[4-[3-(2-nitro-ph
enoxy)-propoxy]-phenyl]-piperidin-3-yloxy]-3-[1,2,4]triazol-1-yl-propan-2-o
l as colorless oil; MS: 684 (M+H).sup.+.
Example 10
(R)-1-imidazol-1-yl-3-[(3S,4R,5R)-5-(4-methoxy-naphthalen-2-ylmethoxy)-4-[3
-(2-nitro-phenoxy)-propoxy]-phenyl]-piperidin-3-yloxy]-propan-2-ol
(a) In analogy to the procedure described in example 1) (k) the
(3R,4R,5S)-3-(4-methoxy-naphthalen-2-ylmethoxy)-4-[4-[3-(2-nitro-phenoxy)-
propoxy]-phenyl]-5-[(2R)-oxiranylmethoxy]-piperidine-1-carboxylic
acid tert-butyl ester was treated with imidazol and sodium hydride
in N,N-dimethylformamide to yield the
(3S,4R,5R)-3-[(2R)-2-hydroxy-3-imidazol-1-yl-propoxy)-5-(4-methoxy-naphtha
len-2-ylmethoxy)-4-[4-[3-(2-nitro-phenoxy)-propoxy]-phenyl]-piperidine-1-ca
rboxylic acid tert-butyl ester as colorless oil; MS: 783
(M+H).sup.+.
(b) In analogy to the procedure described in example 1) (1) the
(3S,4R,5R)-3-[(2R)-2-hydroxy-3-imidazol-1-yl-propoxy)-5-(4-methoxy-naphtha
len-2-ylmethoxy)-4-[4-[3-(2-nitro-phenoxy)-propoxy]-phenyl]-piperidine-1-ca
rboxylic acid tert-butyl ester was deprotected with HCl in methanol
to yield the
(R)-1-imidazol-1-yl-3-[(3S,4R,5R)-5-(4-methoxy-naphthalen-2-ylmethoxy)-4-[
4-[3-(2-nitro-phenoxy)-propoxy]-phenyl]-piperidin-3-yloxy]-propan-2-ol
as colorless foam; MS: 683 (M+H).sup.+.
Example 11
(R)-3-[(3S,4R,5R)-4-[4-[3-(5-fluoro-2-methoxy-benzyloxy)-propoxy]-phenyl]-5
-(4-methoxy-naphthalen-2-ylmethoxy]-piperidin-3-yloxy]-propane-1,2-diol
(a) In analogy to the procedure described in example 1) (e) the
(3S,4R,5R)-3-[(4S)-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-5-hydroxy-4-(4
-hydroxy-phenyl)-piperidine-1-carboxylic acid tert-butyl ester was
treated with allyl bromide in N,N-dimethylformamide in the presence
of potassium carbonate to yield the
(3S,4R,5R)-4-(4-allyloxy-phenyl)-3-[(4S)-2,2-dimethyl-[1,3]dioxolan-4-ylme
thoxy]-5-hydroxy-piperidine-1-carboxylic acid tert-butyl ester as
colorless oil; MS: 464 (M+H).sup.+.
(b) In analogy to the procedure described in example 1) (f) the
(3S,4R,5R)-4-(4-allyloxy-phenyl)-3-[(4S)-2,2-dimethyl-[1,3]dioxolan-4-ylme
thoxy]-5-hydroxy-piperidine-1-carboxylic acid tert-butyl ester was
reacted with 3-chloromethyl-1-methoxy-naphthalene [example 1)
(.alpha.)] to yield the
(3S,4R,5R)-4-(4-allyloxy-phenyl)-3-[(S)-2,2-dimethyl-[1,3]dioxolan-4-ylmet
hoxy]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic
acid tert-butyl ester as colorless oil; MS: 634(M+H).sup.+.
(c) 0.40 g (0.63 mmol) of
(3S,4R,5R)-4-(4-allyloxy-phenyl)-3-[(S)-2,2-dimethyl-[1,3]dioxolan-4-ylmet
hoxy]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic
acid tert-butyl ester, 1.4 mg (0.0063 mmol) of palladium-II-acetate
and 3.3 mg (0.0126 mmol) of triphenylphosphin were dissolved in 2
ml of tetrahydrofuran. After cooling to 5.degree. C., 21.7 mg
(0.947 mmol) of lithiumborohydride were added and the reaction
mixture stirred for 4 hours without cooling. Thereafter, the
reaction mixture was again cooled to 5.degree. C. and treated with
0.32 ml of acetone, then diluted with 5 ml of saturated sodium
hydrogen carbonate solution and extracted twice with 5 ml of ether.
The combined organic phases were washed once with a small amount of
water, dried over magnesium sulphate, evaporated under reduced
pressure and dried in a high vacuum. The thus-obtained crude
product was separated on silica gel using a mixture of
dichloromethane/ethyl acetate (4/1) as the eluent and yielded 0.343
g (0.578 mmol), 91.5%,
(3S,4R,5R)-3-[(4S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-4-(4-hydroxy-ph
enyl)-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic
acid tert-butyl ester as colorless oil; MS: 594 (M+H).sup.+.
(d) In analogy to the procedure described in example 1 (e) the
(3S,4R,5R)-3-[(4S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-4-(4-hydroxy-ph
enyl)-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic
acid tert-butyl ester was treated with the
2-(3-chloro-propoxymethyl)-4-fluoro-1-methoxy-benzene [example 11
(.alpha.)] to yield the
(3S,4R,5R)-3-[(4S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-4-[4-[3-(5-fluo
ro-2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-methoxy-naphthalen-2-ylmethox
y)-piperidine-1-carboxylic acid tert-butyl ester as light yellow
oil; MS: 790 (M+H).sup.+.
(e) In analogy to the procedure described in example 1) (g) the
(3S,4R,5R)-3-[(4S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-4-[4-[3-(5-fluo
ro-2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-methoxy-naphthalen-2-ylmethox
y)-piperidine-1-carboxylic acid tert-butyl ester was deprotected
with HCl in methanol to yield the
(R)-3-[(3S,4R,5R)-4-[4-[3-(5-fluoro-2-methoxy-benzyloxy)-propoxy]-phenyl]-
5-(4-methoxy-naphthalen-2-ylmethoxy]-piperidin-3-yloxy]-propane-1,2-diol
as amorphous solid; MS: 650 (M+H).sup.+.
Preparation of
2-(3-chloro-propoxymethyl)-4-fluoro-1-methoxy-benzene
(a) 0.870 g (5.00 mmol) of
2-chloromethyl-4-fluoro-1-methoxy-benzene [B. Maziere, N.
Dat-Xuong, Chim. Ther. (3), 1-9(1968)] and 0.83 ml of
3-chloro-1-propanol were dissolved in 4.8 ml of
N,N-dimethylformamide. 0.267 g (6.23 mmol) of sodium hydride (55%
dispersion in mineral oil) was added in small portions over 2 hours
keeping the temperature at 10-15.degree. C. After 1 hour stirring
at room temperature, 0.032 g (0.75 mmol) of sodium hydride
dispersion was added and the mixture stirred another 3 hours.
Thereupon, the reaction mixture was poured into 50 ml of ice-water
and extracted three times with 100 ml of ether. The combined ether
phases were subsequently washed with water, dried over magnesium
sulphate and evaporated on a rotary evaporator at a maximum
40.degree. C. The residue (1.5 g) which was thereby obtained was
chromatographed on silica gel with dichloromethane/hexane (1:1).
There was thus obtained 0.928 g (3.99 mmol), 80%,
2-(3-chloro-propoxymethyl)-4-fluoro-1-methoxy-benzene as a
colorless oil: MS: 232, 234 (M).sup.+.
Example 12
(R)-3-[(3S,4R,5R)-4-[4-[3-(2-chloro-phenoxy)-propoxy]-phenyl]-5-(4-methoxy-
naphthalen-2-ylmethoxy)-piperidin-3-yloxy]-propane-1,2-diol
(a) In analogy to the procedure described in example 1) (e) the
(3S,4R,5R)-3-[(4S)-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-5-hydroxy-4-(4
-hydroxy-phenyl)-piperidine-1-carboxylic acid tert-butyl ester was
treated with the 1-(3-brom-propoxy)-2-chlor-benzol (WO97/09311) to
yield the
(3S,4R,5R)-4-[4-[3-(2-chloro-phenoxy)-propoxy]-phenyl]-3-[(4S)-2,2-dimethy
l-[1,3]dioxolan-4-ylmethoxy]-5-hydroxy-piperidine-1-carboxylic acid
tert-butyl ester as colorless oil; MS: 592.3 (M+H).sup.+.
(b) In analogy to the procedure described in example 1) (f) the
(3S,4R,5R)-4-[4-[3-(2-chloro-phenoxy)-propoxy]-phenyl]-3-[(4S)-2,2-dimethy
l-[1,3]dioxolan-4-ylmethoxy]5-hydroxy-piperidine-1-carboxylic acid
tert-butyl ester was reacted with the
3-chloromethyl-1-methoxy-naphthalene [example 1) (.alpha.)] to
yield the
(3S,4R,5R)-4-[4-[3-(2-chloro-phenoxy)-propoxy]-phenyl]-3-[(4S)-2,2-dimethy
l-[1,3]dioxolan-4-ylmethoxy]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin
e-1-carboxylic acid tert-butyl ester as colorless oil; MS: 762.3
(M+H).sup.+.
(c) In analogy to the procedure described in example 1 (g) the
(3S,4R,5R)-4-[4-[3-(2-chloro-phenoxy)-propoxy]-phenyl]-3-[(4S)-2,2-dimethy
l-[1,3]dioxolan-4-ylmethoxy5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-
1-carboxylic acid tert-butyl ester was deprotected with HCl in
methanol to yield the
(R)-3-[(3S,4R,5R)-4-[4-[3-(2-chloro-phenoxy)-propoxy]-phenyl]-5-(4-methoxy
-naphthalen-2-ylmethoxy)-piperidin-3-yloxy]-propane-1,2-diol as
colorless oil; MS: 622.2 (M+H).sup.+.
Example 13
(R)-3-[(3S,4R,5R)-4-[4-[3-(2-Methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-metho
xy-naphthalen-2-ylmethoxy)-piperidin-3-ylmethoxy]-propane-1,2-diol
(a) To a hot solution of 40.2 g (70.6 mmol) of
(3RS,4RS,5SR)-1-benzyl-4-(4-methoxy-phenyl)-5-trityloxymethyl-piperidin-3-
ol [WO 9709311, Example 148 (c)] in 600 ml of ethyl acetate and 200
ml of methanol, 6.4 g (42.3 mmol) of L(+)-mandelic acid, dissolved
in 20 ml of methanol, were added and the mixture heated to reflux.
The solvent was distilled off until the first solid material
appeared. Then, under stirring the solution was cooled to room
temperature. The solid formed was filtered and dried under vacuum.
After two crystallizations 17.2 g of
(3R,4R,5S)-1-benzyl-4-(4-methoxy-phenyl)-5-trityloxymethyl-piperidin-3-ol
(S)-hydroxy-phenyl-acetate were obtained as colorless crystals;
e.e. >99.5% (The optical purity was determined by gas
chromatography after hydrogenolysis with palladium-on-charcoal in
methanol and treatment with hydrogenchloride in methanol to obtain
the unprotected derivative which was then trifluoroacetylated).
(b) 33.3 (46.13 mmol) of
(3R,4R,5S)-1-benzyl-4-(4-methoxy-phenyl)-5-trityloxymethyl-piperidin-3-ol
(S)-hydroxy-phenyl-acetate were treated with a cold aqueous
solution of 7.3 g (69.2 mmol) of sodium carbonate in 100 ml water
and 600 ml of ethyl acetate. The aqueous phase was separated and
extracted twice with 200 ml of ethyl acetate. The combined organic
phases were dried over sodium sulfate and evaporated under reduced
pressure to yield 25 g of
(3R,4R,5S)-1-benzyl-4-(4-methoxy-phenyl)-5-trityloxymethyl-piperidin-3-ol
as a colorless oil which was directly used without further
purification.
The crude base was dissolved in 800 ml of dichloromethane and
cooled to -78.degree. C. Thereupon, 131.5 ml (131.5 mmol) of
borotribromide (1 M in dichloromethane) were added dropwise under
stirring so that the temperature was kept at about -65.degree. C.
After complete addition, the reaction mixture was left to warm up
during the night. To complete the reaction another 43.8 ml (43.83
mmol) of borotribromide were added under the aforementioned
conditions, and after additional 7 hours of stirring at room
temperature the reaction was complete. Then the reaction mixture
was cooled to 0.degree. C. and the precipitated product was
isolated by filtration. The mother liquor was concentrated to half
of its volume and cooled to 0.degree. C. and a second crop of solid
product was obtained. The combined fractions were dried under high
vacuum during 15 hours at room temperature to give 18.8 g of
(3R,4R,5S)-1-benzyl-5-hydroxymethyl-4-(4-hydroxy-phenyl)-piperidin-3-ol
hydrobromide [MS: 314 (M+H).sup.+ ] as a yellowish solid. The crude
product was used in the next step without further purification.
(c) The solution of 18.6 g (47.2 mmol) of crude
(3R,4R,5S)-1-benzyl-5-hydroxymethyl-4-(4-hydroxy-phenyl)-piperidin-3-ol
hydrobromide in 250 ml of methanol was flushed with argon, treated
with 1.5 g of palladium-on-charcoal (10%) and exhaustively
hydrogenated at room temperature under normal pressure during 18
hours The reaction mixture was filtered over Dicalit and the
residue washed twice with 100 ml of warm methanol. The methanol
solutions were combined and evaporated under reduced pressure to
yield 12.79 g of
(3R,4R,5S)-5-hydroxymethyl-4-(4-hydroxy-phenyl)-piperidin-3-ol
hydrobromide [MS: 223 (M).sup.+ ] as a yellowish foam which was
used in the next step without further purification.
(d) 12.79 g (42.05 mmol) of the crude
(3R,4R,5S)-5-hydroxymethyl-4-(4-hydroxy-phenyl)-piperidin-3-ol
hydrobromide and 7.1 g (84.1 mmol) of hydrogencarbonate were
dispersed in 60 ml of water and 60 ml of dioxane. A solution of 9.6
g (44.1 mmol) of di-tert-butyl-dicarbonate in 60 ml of dioxane was
added dropwise at room temperature. After complete addition
stirring was continued for 18 hours at room temperature. Then the
reaction mixture was diluted with 300 ml of water and extracted
with 300 ml of ethyl acetate. The aqueous phase was separated and
extracted twice with 150 ml of ethyl acetate. The combined organic
phases were dried over sodium sulfate and evaporated under reduced
pressure. The residue which was thereby obtained was
chromatographed on silica gel with a 95:5 mixture of
dichloromethane and methanol. There where thus obtained 11.2 g of
(3R,4R,5S)-3-hydroxy-5-hydroxymethyl-4-(4-hydroxy-phenyl)-piperidine-1-car
boxylic acid tert-butyl ester in the form of a yellowish foam; MS:
324 (M+H).sup.+.
(e) 11.2 g (34.63 mmol) of
(3R,4R,5S)-3-hydroxy-5-hydroxymethyl-4-(4-hydroxy-phenyl)-piperidine-1-car
boxylic acid tert-butyl ester were stirred together with 7.7 g
(55.41 mmol) of potassium carbonate and 8.9 g (1.2 moleq) of
1-(3-chloro-propoxymethyl)-2-methoxy-benzene in
N,N-dimethylformamide at 100-110.degree. C. during 18 hours. To
complete the reaction another 1.5 g (0.2 moleq) of
1-(3-chloro-propoxymethyl)-2-methoxy-benzene were added and the
mixture was stirred at 100-110.degree. C. during additional 12
hours. Thereupon the reaction mixture was cooled to room
temperature, then diluted with 540 ml of water and 400 ml of
dichloromethane. The aqueous phase was separated and extracted
twice with 250 ml of dichloromethane. The combined organic phases
were dried over sodium sulfate and evaporated under reduced
pressure. The residue which was thereby obtained was
chromatographed on silica gel with a 98:2 mixture of
dichloromethane and methanol as the eluent. There where thus
obtained 16.2 g of
(3R,4R,5S)-3-hydroxy-5-hydroxymethyl-4-[4-[3-(2-methoxy-benzyloxy)-propoxy
]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester in the form
of a yellowish foam; MS: 524 (M+Na).sup.+.
(f) To a solution of 16.1 g (32.1 mmol) of
(3R,4R,5S)-3-hydroxy-5-hydroxymethyl-4-[4-[3-(2-methoxy-benzyloxy)-propoxy
]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester in 80 ml of
pyridine, 11 g (38.5 mmol) of triphenylchloromethane and 0.04 g
(0.31 mmol) of 4-dimethylaminopyridine were added. The solution was
stirred at room temperature for 60 hours. For the working-up the
reaction mixture was evaporated under reduced pressure and the
residue which was thereby obtained was dissolved in 900 ml of
dichloromethane. The organic phase was washed with 250 ml of water,
then dried over sodium sulfate and evaporated under reduced
pressure. The crude material was chromatographed on silica gel with
a 98:2 mixture of dichloromethane and methanol as the eluent. There
were thus obtained 16.3 g of
(3R,4R,5S)-3-hydroxy-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-trit
yloxymethyl-piperidine-1-carboxylic acid tert-butyl ester in the
form of an colorless oil; MS: 766 (M+Na).sup.+.
(g) Under an argon atmosphere 16.2 g (21.7 mmol) of
(3R,4R,5S)-3-hydroxy-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-trit
yloxymethyl-piperidine-1-carboxylic acid tert-butyl ester and 5.8 g
(28.3 mmol) of 3-chloromethyl-1-methoxy-naphthalen [WO 9709311]
were dissolved in 150 ml of N,N-dimethylformamide, treated at
0.degree. C. with 1.7 g (about 34.8 mmol) of sodium hydride
dispersion in refined oil (55-65%), and the reaction mixture was
warmed to room and stirred for 15 hours. Thereupon the
N,N-dimethylformamide was evaporated under reduced pressure and the
residue which was thereby obtained was hydrolyzed by 200 ml of
ice-water and extracted with 500 ml of dichloromethane. The aqueous
phase was separated and extracted twice with 200 ml of
dichloromethane. The combined organic phases were dried over sodium
sulfate and evaporated under reduced pressure. The residue which
was thereby obtained was chromatographed on silica gel with
dichloromethane. There where thus obtained 18.4 g of
(3R,4R,5S)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-3-(4-methoxy-nap
hthalen-2-ylmethoxy)-5-trityloxymethyl-piperidine-1-carboxylic acid
tert-butyl ester in the form of a yellowish oil; MS: 937
(M+Na).sup.+.
(h) To the solution of 18.3 g (20.1 mmol) of
(3R,4R,5S)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-3-(4-methoxy-nap
hthalen-2-ylmethoxy)-5-trityloxymethyl-piperidine-1-carboxylic acid
tert-butyl ester in 200 ml of dichloromethane was poured under
stirring at room temperature a solution of 9.4 g (80.4 mmol) of
trifluoroacetic acid and 17.2 g (80.4 mmol) of trifluoroacetic acid
anhydride in 20 ml of dichloromethane. After 30-40 seconds the
reaction flask was placed in a dry ice/acetone mixture and
simultaneously 61.3 g (603.3 mmol) of triethylamine were added, and
stirring was continued at 0.degree. C. for 5 minutes. Then 80 ml of
methanol were added and stirring was continued for 15 minutes.
Thereupon the reaction mixture was treated with 200 ml of a
saturated solution of sodium hydrogencarbonate and 500 ml of
dichloromethane. The aqueous phase was separated and extracted two
times with 150 ml of dichloromethane. The combined organic phases
were dried over sodium sulfate and evaporated under reduced
pressure to yield 19 g of the crude alcohol. The residue which was
thereby obtained was chromatographed on silica gel with a 98:2
mixture of dichloromethane and methanol as the eluent. There where
thus obtained 12.9 g of
(3S,4R,5R)-3-hydroxymethyl-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-
5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid
tert-butyl ester in the form of a yellowish oil; MS: 694
(M+Na).sup.+.
(i) To the solution of 2.0 g of
(3S,4R,5R)-3-hydroxymethyl-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-
5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid
tert-butyl ester in 50 ml of N,N-dimethylformamide were added 1.1 g
(about 23.8 mmol) of sodium hydride dispersion in refined oil
(55-65%), and the reaction mixture was heated to 50.degree. C.
under argon for 1 hour. Then, 6.8 g (23.8 mmol) of
(R)-(-)-2,2-dimethyl-4-(hydroxymethyl)-1,3-dioxolane-p-toluene
sulfonate were added and stirring was continued at 50.degree. C.
for another 3 hours. Subsequently, the reaction mixture was
evaporated under reduced pressure and the residue which was
obtained was hydrolyzed with 50 ml of ice-water and extracted with
100 ml of dichloromethane. The aqueous phase was separated and
extracted twice with 50 ml of dichloromethane. The combined organic
phases were dried over sodium sulfate and then evaporated under
reduced pressure. The residue which was thereby obtained was
chromatographed on silica gel with a 99:1 mixture of
dichloromethane and methanol as the eluent. There where thus
obtained 1.3 g of
(3S,4R,5R)-3-[(S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxymethyl]-4-[4-[3-(2
-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-p
iperidine-1-carboxylic acid tert-butyl ester in the form of a
yellowish oil; MS: 803 (M+NH.sub.4).sup.+.
(j) A solution of 4.7 g (6 mmol) of
(3S,4R,5R)-3-[(S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxymethyl]-4-[4-[3-(2
-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-p
iperidine-1-carboxylic acid tert-butyl ester in 50 ml of methanol
and 44.4 ml of 2.7M hydrogenchloride in methanol was stirred at
room temperature for 1 hour. Subsequently, the reaction mixture was
cooled to 0.degree. C. and 20.1 g (239 mmol) of solid sodium
hydrogencarbonate were added. Stirring was continued as long as
carbondioxide was formed and the reaction mixture had reached room
temperature. Then the mixture was adjusted to pH 8-9 by addition of
2 N sodium hydroxide solution and diluted with 250 ml of
dichloromethane. The aqueous phase was separated and the organic
phase dried over sodium sulfate and finally evaporated under
reduced pressure. The residue which was thereby obtained was
chromatographed on silica gel with a 90:10:0.1 mixture of
dichloromethane, methanol and ammonium hydroxide as the eluent.
There where thus obtained 2.7 g of
(R)-3-[(3S,4R,5R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-meth
oxy-naphthalen-2-ylmethoxy)-piperidin-3-ylmethoxy]-propane-1,2-diol
in the form of an amorphous solid MS: 646 (M+H).sup.+.
Example 14
(3S,4R,5R)-[4-[4-[3-(2-Methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-methoxy-nap
hthalen-2-ylmethoxy)-piperidin-3-yl]-methanol
In an analogous manner to that described in Example 13 (j) by
cleavage of the BOC group using a solution of hydrogen chloride in
methanol, starting from
(3S,4R,5R)-3-hydroxymethyl-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-
5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid
tert-butyl ester [Example 13 (h)] there was obtained
(3S,4R,5R)-[4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-methoxy-na
phthalen-2-ylmethoxy)-piperidin-3-yl]-methanol as a colorless foam;
MS: 572 (M+H).sup.+.
Example 15
(3S,4R,5R)-3-Imidazol-1-ylmethyl-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phe
nyl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine
dihydrochloride
(a) To a solution of 1.5 g (2.2 mmol) of
(3S,4R,5R)-3-hydroxymethyl-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-
5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid
tert-butyl ester [Example 13 (h)] in 40 ml of tetrahydrofurane were
added 0.9 ml (6.7 mmol) of triethylamine and thereafter dropwise at
0.degree. C. 512 mg (4.5 mmol) of methanesulphonyl chloride. The
reaction solution was stirred at room temperature for 2 hours. For
the working-up, the reaction solution was diluted with 50 ml of
dichloromethane, extracted with 20 ml of saturated sodium
hydrogencarbonate solution, dried over sodium sulfate and
evaporated under reduced pressure. The solid crude mesylate was
dissolved in 30 ml of N,N-dimethylformamide and thereafter added
dropwise to a solution beforehand prepared of 456 mg (6.7 mmol) of
imidazole and 322 mg (about 6.7 mmol) of sodium hydride dispersion
in refined oil (55-65%) in 10 ml of N,N-dimethylformamide. The
reaction mixture was stirred at 100.degree. C. for 6 hours and
thereafter evaporated under reduced pressure. The residue was taken
up in 50 ml of dichloromethane and then extracted with 20 ml of
saturated sodium hydrogencarbonate solution. The organic phase was
separated and dried over sodium sulfate and subsequently evaporated
under reduced pressure. For purification, the crude product was
chromatographed on silica gel using a 98:2 mixture of
dichloromethane and methanol as the eluent. There were obtained 1.4
g of
(3R,4R,5R)-3-imidazol-1-ylmethyl-4-{4-[3-(2-methoxy-benzyloxy)-propoxy]-ph
enyl}-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic
acid tert-butyl ester as a yellowish foam; MS: 722 (M+H).sup.+.
(b) In an analogous manner to that described in Example 13 (j) by
cleavage of the BOC group using a solution of hydrogen chloride in
methanol, starting from
(3R,4R,5R)-3-imidazol-1-ylmethyl-4-{4-[3-(2-methoxy-benzyloxy)-propoxy]-ph
enyl}-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic
acid tert-butyl ester there was obtained
(3S,4R,5R)-3-imidazol-1-ylmethyl-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-ph
enyl]-5-4-methoxy-naphthalen-2-ylmethoxy)-piperidine
dihydrochloride as an amorphous solid; MS: 622 (M+H).sup.+.
Example 16
Mixture of (RS)- and
(SR)-3-[(3SR,4RS,5RS)-4-[4-(3-Benzyloxy-propoxy)-phenyl]-5-(naphthalen-2-y
lmethoxy)-piperidin-3-ylmethoxy]-propane-1,2-diol
(a) In an analogous manner to that described in Example 13 (g), by
alkylating
(3SR,4RS,5RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-hydroxymethyl-5-(naphth
alen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester [WO
9709311, Example 148 (h)] with allylbromide there was obtained
(3SR,4RS,5RS)-3-allyloxymethyl-4-[4-(3-benzyloxy-propoxy)-phenyl]-5-(
naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl
ester as a colorless solid; MS: 652 (M+H).sup.+.
(b) A solution of 91 mg (0.3mmol) of potassium peroxodisulfate, 3.0
mg (0.009 mmol) of potassium ferrocyanide, 1.1 mg (0.003 mmol) of
potassium osmate dihydrate and 84 mg (0.6 mmol) of potassium
carbonate in 1 ml of water was stirred at room temperature for 20
minutes and thereafter cooled to 0.degree. C. Thereto were added
7.2 mg (0.07 mmol) of methanesulfonamide and a solution of 198 mg
(0.3 mmol) of
(3SR,4RS,5RS)-3-allyloxymethyl-4-[4-(3-benzyloxy-propoxy)-phenyl]-5-(napht
halen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester in
2 ml of tert-butanol. After the complete addition, stirring was
continued at room temperature for 48 hours. The mixture was diluted
with 5 ml of sodium sulfite solution (0.2 N) and 2 ml of water and
extracted 3 times with 10 ml of dichloromethane each time. The
combined organic phases were washed with 10 ml of saturated sodium
hydrogencarbonate solution, then dried over sodium sulfate and
evaporated under reduced pressure. The thus obtained crude product
was chromatographed on silica gel with a 98:2 mixture of
dichloromethane and methanol as the eluent. There were thus
obtained 153 mg of a mixture of (3RS,4SR,5SR)- and
(3SR,4RS,5RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-[(2RS)-2,3-dihydroxy-pr
opoxymethyl)]-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylic
acid tert-butyl ester as a yellowish oil; MS: 686 (M+H).sup.+.
(c) In an analogous manner to that described in Example 13 (j) by
cleavage of the BOC group using a solution of hydrogen chloride in
methanol, starting from of a mixture of (3RS,4SR,5SR)- and
(3SR,4RS,5RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-[-(2RS)-2,3-dihydroxy-p
ropoxymethyl)]-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylic
acid tert-butyl ester there was obtained a mixture of (RS)- and
(SR)-3-[(3SR,4RS,5RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-5-(naphthalen-2-y
lmethoxy)-piperidin-3-ylmethoxy]-propane-1,2-diol as an amorphous
colorless solid; MS: 586 (M+H).sup.+.
Example 17
Mixture of (RS)- and
(SR)-3-[(3SR,4RS,5RS)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(na
phthalen-2-ylmethoxy)-piperidin-3-ylmethoxy]-propane-1,2-diol
(a) In an analogous manner to that described in Example 13 (e), by
alkylating
(3RS,4RS,5SR)-3-hydroxy-5-hydroxymethyl-4-(4-hydroxy-phenyl)-piperidin-1-c
arbonsaure tert-butylester [WO 9709311, Example 148 (f)] with
1-(3-chloro-propoxymethyl)-2-methoxy-benzene [WO 9709311] there was
obtained
(3RS,4RS,5SR)-3-hydroxy-5-hydroxymethyl-4-[4-[3-(2-methoxy-benzyloxy)-prop
oxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester as an
amorphous colorless solid; MS: 519 (M+NH.sub.4).sup.+.
(b) In an analogous manner to that described in Example 13 (f), by
reacting
(3RS,4RS,5SR)-3-hydroxy-5-hydroxymethyl-4-[4-[3-(2-methoxy-benzyloxy)-prop
oxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester with
triphenylchloromethane there was obtained
(3RS,4RS,5SR)-3-hydroxy-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]5-tr
ityloxymethyl-piperidine-1-carboxylic acid tert-butyl ester as a
colorless foam; MS: 761 (M+NH.sub.4).sup.+.
(c) In an analogous manner to that described in Example 13 (g), by
alkylating
(3RS,4RS,5SR)-3-hydroxy-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-t
rityloxymethyl-piperidine-1-carboxylic acid tert-butyl ester with
2-bromo-methylnaphthalene there was obtained
(3RS,4RS,5SR)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-3-(naphthalen
-2-ylmethoxy)-5-trityloxymethyl-piperidine-1-carboxylic acid
tert-butyl ester as a colorless oil; MS: 907 (M+Na).sup.+.
(d) In an analogous manner to that described in Example 13 (h), by
deprotecting
(3RS,4RS,5SR)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-3-(naphthalen
-2-ylmethoxy)-5-trityloxymethyl-piperidine-1-carboxylic acid
tert-butyl there was obtained
(3SR,4RS,5RS)-3-hydroxymethyl-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-pheny
l]-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid
tert-butyl ester as a yellowish foam; MS: 642 (M+H).sup.+.
(e) In an analogous manner to that described in Example 13 (g), by
alkylating
(3SR,4RS,5RS)-3-hydroxymethyl-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-pheny
l]-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid
tert-butyl ester with allylbromide there was obtained
(3SR,4RS,5RS)-3-allyloxymethyl-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phen
yl]-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid
tert-butyl ester as a colorless oil; MS: 682 (M+H).sup.+.
(f) In an analogous manner to that described in Example 16 (b), by
hydroxylating
(3SR,4RS,5RS)-3-allyloxymethyl-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phen
yl]-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid
tert-butyl ester there was obtained a mixture of (3SR,4RS,5RS)- and
(3RS,4SR,5SR)-3-[(2RS)-2,3-dihydroxy-propoxymethyl]-4-[4-[3-(2-methoxy-ben
zyloxy)-propoxy]-phenyl]-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylic
acid tert-butyl ester as a colorless oil; MS: 733
(M+NH.sub.4).sup.+.
(g) A solution of 63 mg (0.08 mmol) of a mixture of (3SR,4RS,5RS)-
and
(3RS,4SR,5SR)-3-[(2RS)-2,3-dihydroxy-propoxymethyl]-4-[4-[3-(2-methoxy-ben
zyloxy)-propoxy]-phenyl]-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylic
acid tert-butyl ester in 5 ml of dry dichloromethane was treated
with 57.1 mg (0.25 mmol) of anhydrous zinc bromide and the mixture
was stirred at room temperature for 5 hours. Subsequently, the
solvent was distilled off under reduced pressure, the residue was
taken up in 10 ml of dichloromethane and treated with 4 ml of
saturated sodium hydrogencarbonate solution. Thereafter the organic
phase was dried over sodium sulfate and evaporated under reduced
pressure. For purification, the residue was chromatographed on
silica gel using a 90:10:0.1 mixture of dichloromethane, methanol
and ammonium hydroxide as the eluent. There were obtained 41 mg of
a mixture of (RS)- and
(SR)-3-[(3SR,4RS,5RS)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(na
phthalen-2-ylmethoxy)-piperidin-3-ylmethoxy]-propane-1,2-diol in
the form of a yellowish foam; MS: 616 (M+H).sup.+.
Example 18
(R)-1-[(3S,4R,5R)-4-[4-[3-(5-fluoro-2-methoxy-benzyloxy)-propoxy]-phenyl]-5
-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-3-yloxy]-3-methoxy-propan-2-o
l
(a) 0.500 g (0.789 mmol) of
(3S,4R,5R)-4-(4-allyloxy-phenyl)-3-[(S)-2,2-dimethyl-[1,3]dioxolan-4-ylmet
hoxy]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic
acid tert-butyl ester [example 11 (b)] were dissolved in 7 ml of
absolute methanol at 40.degree. C., cooled to room temperature and
treated with 0.16 ml of aqueous hydrochloric acid (25%). After
stirring for 1 hour, the reaction mixture was neutralized with
solid sodium carbonate, then evaporated. The residue obtained was
redissolved in dichloromethane, filtered and evaporated on a rotary
evaporator at a maximum 40.degree. C. The crude product obtained
was chromatographed on silica gel with dichloromethane/methanol
(95/5). There were thus obtained 0.414 g (0.697 mmol), 88.4%
(3S,4R,5R)-4-(4-allyloxy-phenyl)-3-[(2R)-2,3-dihydroxy-propoxy)-5-(4-metho
xy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl
ester as light yellow oil; MS: 594 (M+H).sup.+.
(b) In analogy to the procedure described in example 1(i) the
(3S,4R,5R)-4-(4-allyloxy-phenyl)-3-[(2R)-2,3-dihydroxy-propoxy)-5-(4-metho
xy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl
ester was treated with toluol-4-sulfochlorid to yield the
(3S,4R,5R)-4-(4-allyloxy-phenyl)-3-[(2S)-2-hydroxy-3-(toluene-4-sulfonylox
y)-propoxy]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic
acid tert-butyl ester as colorless foam; MS: 748 (M+H).sup.+.
(c) In analogy to the procedure described in example 1(j) the
(3S,4R,5R)-4-(4-allyloxy-phenyl)-3-[(2S)-2-hydroxy-3-(toluene-4-sulfonylox
y)-propoxy]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic
acid tert-butyl ester was treated with sodium hydroxide in
dimethylsulfoxid to yield the
(3R,4R,5S)-4-(4-allyloxy-phenyl)-3-(4-methoxy-naphthalen-2-ylmethoxy)-5-[(
2R)-oxiranylmethoxy]-piperidine-1-carboxylic acid tert-butyl ester
as colorless oil.
(d) In analogy to the procedure described in example 1(k) the
(3R,4R,5S)-4-(4-allyloxy-phenyl)-3-(4-methoxy-naphthalen-2-ylmethoxy)-5-[(
2R)-oxiranylmethoxy]-piperidine-1-carboxylic acid tert-butyl ester
was treated with sodium methylate in N,N-dimethylformamide to yield
the
(3S,4R,5R)-4-(4-allyloxy-phenyl)-3-[(2R)-2-hydroxy-3-methoxy-propoxy]-5-(4
-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid
tert-butyl ester as colorless oil; MS: 608 (M+H).sup.+.
(e) In analogy to the procedure described in example 11(c) the
(3S,4R,5R)-4-(4-allyloxy-phenyl)-3-[(2R)-2-hydroxy-3-methoxy-propoxy]-5-(4
-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid
tert-butyl ester was treated with palladium-II-acetate,
triphenylphosphin and lithiumborohydride in tetrahydrofuran to
yield the
(3S,4R,5R)-3-[(2R)-2-hydroxy-3-methoxy-propoxy]-4-(4-hydroxy-phenyl)-5-(4-
methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid
tert-butyl ester as colorless oil; MS: 568 (M+H).sup.+.
(f) In analogy to the procedure described in example 1(e) the
(3S,4R,5R)-3-[(2R)-2-hydroxy-3-methoxy-propoxy]-4-(4-hydroxy-phenyl)-5-(4-
methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid
tert-butyl ester was treated with the
2-(3-chloro-propoxymethyl)-4-fluoro-1-methoxy-benzene [example
11(.alpha.)] to yield the
(3S,4R,5R)-4-[4-[3-(5-fluoro-2-methoxy-benzyloxy)-propoxy]-phenyl]-3-[(2R)
-2-hydroxy-3-methoxy-propoxy]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidi
ne-1-carboxylic acid tert-butyl ester as colorless oil; MS: 764
(M+H).sup.+.
(g) In analogy to the procedure described in example 1(l) the
(3S,4R,5R)-4-{4-[3-(5-fluoro-2-methoxy-benzyloxy)-propoxy]-phenyl}-3-[(2R)
-2-hydroxy-3-methoxy-propoxy]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidi
ne-1-carboxylic acid tert-butyl ester was deprotected with
hydrochloric acid in methanol to yield the
(R)-1-[(3S,4R,5R)-4-[4-[3-(5-fluoro-2-methoxy-benzyloxy)-propoxy]-phenyl]-
5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-3-yloxy]-3-methoxy-propan-2-
ol as colorless oil; MS: 664 (M+H).sup.+.
Example 19
The following compounds were obtained in an analogous manner to
that described in example 18 and example 1 respectively by
alkylation of the
(3S,4R,5R)-3-[(2R)-2-hydroxy-3-methoxy-propoxy]-4-(4-hydroxy-phenyl)-5-(4-
methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid
tert-butyl ester followed by cleavage of the protecting group by
means of hydrogen chloride in methanol:
1) by alkylation with
1-(3-chloro-propoxymethyl)-4-fluoro-2-methoxy-benzene and
subsequent cleavage of the BOC group,
(R)-1-[(3S,4R,5R)-4-[4-[3-(4-fluoro-2-methoxy-benzyloxy)-propoxy]-phenyl]-
5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-3-yloxy]-3-methoxy-propan-2-
ol as a colorless oil; MS: 664 (M+H).sup.+ ;
2) by alkylation with
1-(3-chloro-propoxymethyl)-3-fluoro-2-methoxy-benzene and
subsequent cleavage of the BOC group,
(R)-1-[(3S,4R,5R)-4-[4-[3-(3-fluoro-2-methoxy-benzyloxy)-propoxy]-phenyl]-
5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-3-yloxy]-3-methoxy-propan-2-
ol as a light yellow oil; MS: 664 (M+H).sup.+ ;
3) by alkylation with
1-(3-chloro-propoxymethyl)-3,5-difluoro-2-methoxy-benzene and
subsequent cleavage of the BOC group,
(R)-1-(3S,4R,5R)-4-[4-[3-(3,5-difluoro-2-methoxy-benzyloxy)-propoxy]-pheny
l]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-3-yloxy]-3-methoxy-propan
-2-ol as a colorless oil; MS: 682 (M+H).sup.+ ;
4) by alkylation with
1-(3-chloro-propoxymethyl)-4,5-difluoro-2-methoxy-benzene and
subsequent cleavage of the BOC group,
(R)-1-](3S,4R,5R)-4-[4-[3-(4,5-difluoro-2-methoxy-benzyloxy)-propoxy]-phen
yl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-3-yloxy]-3-methoxy-propa
n-2-ol as a light yellow oil; MS: 682 (M+H).sup.+.
The 1-(3-chloro-propoxymethyl)-benzene derivatives used as the
alkylating agents were prepared as follows:
1-(3-Chloro-propoxymethyl)-4-fluoro-2-methoxy-benzene
(a) To a solution of 1.3 g (9.3 mmol) of
4-fluoro-2-hydroxy-benzaldehyde, obtained following the method
described by R. Alfred et al. in J. Chem. Soc., Perkin Trans.
(1994), 1823, in 20 ml of acetone were added 0.87 ml (13.4 mmol) of
methyliodide and 1.9 g (13.4 mmol) of powdered potassium carbonate.
The dispersion was stirred at 45.degree. C. for 2 hours.
Subsequently, the reaction mixture was evaporated, the residue
extracted with dichloromethane and water, the organic phase
separated and concentrated under reduced pressure. There was
obtained 1.1 g (77% of theory) of 4-fluoro-2-methoxy-benzaldehyde
as a yellow solid; M: 154 (M).sup.+.
(b) An ice-cold solution of 5.6 g of
4-fluoro-2-methoxy-benzaldehyde in 75 ml of methanol was treated
portionwise (5 portions within 50 minutes) with 1.51 g (40 mmol) of
sodium borohydride and the reaction mixture was stirred for another
1 hour at room temperature. A dispersion of 7 g of potassium
hydrogencarbonate in 20 ml of water was added and the mixture
stirred for 30 minutes at room temperature. Thereupon, most of the
methanol was evaporated under reduced pressure and the residue
extracted with dichloromethane. The organic phase was separated,
dried and concentrated under reduced pressure to yield 5.15 g (91%
of theory) of (4-fluoro-2-methoxy-phenyl)-methanol as a white
solid; MS: 156 (M).sup.+.
(c) To a solution of 1.1 g (7 mmol) of
(4-fluoro-2-methoxy-phenyl)-methanol and 0.85 g (8.4 mmol) of
triethylamine in 10 ml of dichloromethane was added dropwise under
an argon atmosphere at -10.degree. C. a solution of 0.96 g (8.4
mmol) of mesylchloride in 10 ml of dichloromethane. After complete
addition, the reaction mixture was stirred at room temperature for
18 hours. Thereupon, the solution was extracted two times with
water and the organic phase was evaporated under reduced pressure.
The residue was dissolved in 10 ml of tetrahydrofuran, treated with
2 ml of saturated aqueous sodium hydrogencarbonate solution and
stirred for one hour at room temperature.
Subsequently, the mixture was extracted with dichloromethane, the
organic phase separated, dried over sodium sulfate and evaporated
under reduced pressure. The thus obtained crude product was
chromatographed on silica gel with a 1:1 mixture of hexane and
dichloromethane as the eluent. There was thus obtained 0.95 g (60%
of theory) of 1-chloromethyl-4-fluoro-2-methoxy-benzene as a
colorless liquid; MS: 174 (M).sup.+.
(d) To an ice-cold solution of 0.36 g (2.06 mmol) of
1-chloromethyl-4-fluoro-2-methoxy-benzene and 0.195 g (4.12 mmol)
of 1-chloro-3-propanol in 3 ml of dry N,N-dimethyl-formamide were
added 92.5 mg (3.09 mmol) of sodium hydride (80% dispersion in
refined oil) in 3 portions at one hour intervals. After complete
addition the stirring was continued for 2 hours at room
temperature, then 2 ml of an saturated aqueous sodium
hydrogencarbonate solution were added and the reaction mixture
evaporated under reduced pressure. Subsequently, the residue was
treated with a mixture of dichloromethane and water, the organic
phase was separated and dried over sodium sulfate. Finally, the
solvent was evaporated under reduced pressure and the crude product
was purified by chromatography on silica gel with a 1:1 mixture of
hexane and dichloromethane as the eluent. There were obtained 0.29
g (60% of theory) of
1-(3-chloro-propoxymethyl)-4-fluoro-2-methoxy-benzene as a
colorless liquid; MS: 232 (M).sup.+.
1-(3-Chloro-propoxymethyl)-3-fluoro-2-methoxy-benzene
(a) In an analogous manner to that described in (.beta.)
3-fluoro-2-hydroxy-benzaldehyde was reduced by sodium borohydride
to yield 2-fluoro-6-hydroxymethyl-phenol as a white solid; MS: 142
(M).sup.+.
(b) In an analogous manner to that described in (.alpha.)
2-fluoro-6-hydroxymethyl-phenol was alkylated with methyliodide to
yield (3-fluoro-2-methoxy-phenyl)-methanol as a white solid; MS:
142 (M).sup.+.
(c) In an analogous manner to that described in (.gamma.)
(3-fluoro-2-methoxy-phenyl)-methanol was treated with mesylchloride
to obtain 1-chloromethyl-3-fluoro-2-methoxy-benzene as a colorless
liquid; MS: 174 (M).sup.+.
(d) In an analogous manner to that described in (.delta.)
1-chloromethyl-3-fluoro-2-methoxy-benzene was reacted with
1-chloro-3-propanol to yield
1-(3-chloro-propoxymethyl)-3-fluoro-2-methoxy-benzene as a
colorless liquid; MS: 232 (M).sup.+.
1-(3-Chloro-propoxymethyl)-3,5-difluoro-2-methoxy-benzene
(a) In an analogous manner to that described in (.alpha.)
1-(3,5-difluoro-2-hydroxy-phenyl)-ethanone was alkylated with
methyliodide to yield 1-(3,5-difluoro-2-methoxy-phenyl)-ethanone as
beige needles; MS: 186 (M).sup.+.
(b) The 1-(3,5-difluoro-2-methoxy-phenyl)-ethanone was transformed
by an Einhorn reaction following a typical procedure given in
Organikum, 18.sup.th ed., p.375 (Dt. Verlag der Wissenschaften)
into the 3,5-difluoro-2-methoxy-benzaldehyde, which was obtained as
colorless crystals; MS: 188 (M).sup.+.
(c) To an ice-cold solution of 1.7 g (9.03 mmol) of
3,5-difluoro-2-methoxy-benzaldehyde in 10 ml of dry tetrahydrofuran
was added under an argon atmosphere 1 ml of borane dimethylsulfide
complex. The reaction mixture was warmed up and stirred for 24
hours at room temperature. Thereupon, the mixture was again cooled
to 0.degree. C. and 5 ml of methanol were added dropwise within 30
minutes. Subsequently, the solvent was distilled and the crude
product was purified by chromatography on silica gel with a 1:1
mixture of diethylether and dichloromethane as the eluent. There
were obtained 0.89 g (56% of theory) of
(3,5-difluoro-2-methoxy-phenyl)-methanol as a colorless liquid; MS:
174 (M).sup.+.
(d) To a mixture of 0.87 g (5.02 mmol) of
(3,5-difluoro-2-methoxy-phenyl)-methanol, 0.82 ml (7.03 mmol) of
2,6-lutidine, and 0.425 g (10 mmol) of lithium chloride in 5 ml
N,N-dimethylformamide were added dropwise at 0.degree. C. 0.5 ml
(6.5 mmol) of mesylchloride. The suspension was stirred during 18
hours at room temperature and then treated with 1 ml of saturated
aqueous sodium hydrogencarbonate solution. The volatile components
were distilled at 35.degree. C./1 Torr and the residue was
partitioned between ethyl acetate and water. The organic phase was
separated and evaporated under reduced pressure and the crude
product was purified by chromatography on silica gel with
dichloromethane as the eluent. There were obtained 0.49 g (51% of
theory) of 1-chloromethyl-3,5-difluoro-2-methoxy-benzene as a
colorless liquid; MS: 192 (M).sup.+.
(e) In an analogous manner to that described in (8)
1-chloromethyl-3,5-difluoro-2-methoxy-benzene was reacted with
1-chloro-3-propanol to yield
1-(3-chloro-propoxymethyl)-3,5-difluoro-2-methoxy-benzene as a
colorless liquid; MS: 250 (M).sup.+.
1-(3-Chloro-propoxymethyl)-4,5-difluoro-2-methoxy-benzene
(a) To a suspension of 5.75 g (40 mmol) of
1,2-difluoro-4-methoxy-benzene, 2.18 g (72 mmol) of
paraformaldehyde and 3.55 g (25 mmol) of phosphorouspentoxide in 20
ml of acetic acid were added dropwise 7.2 ml of aqueous
hydrochloric acid (37%). Thereupon, the reaction mixture was
stirred for 18 hours at room temperature and additional 4 hours at
60.degree. C. For the working up the mixture was hydrolyzed on
crushed ice and 200 ml of diethylether were added. Under vigorous
stirring 50 ml of saturated aqueous sodium hydrogencarbonate
solution were added dropwise, then solid sodium hydrogencarbonate
was added until the evolvement of carbondioxide had ceased.
Subsequently, the organic phase was separated, extracted with
saturated sodium chloride solution and dried over sodium sulfate.
The solvent was evaporated and the crude product distilled. There
were obtained 7.1 g (92% of theory) of
1-chloromethyl-4,5-difluoro-2-methoxy-benzene as a colorless
liquid; b.p.; 92-93.degree. C. (6 Torr); MS: 192 (M).sup.+.
(b) In an analogous manner to that described in (.delta.)
1-chloromethyl-4,5-difluoro-2-methoxy-benzene was reacted with
1-chloro-3-propanol to yield
1-(3-chloro-propoxymethyl)-4,5-difluoro-2-methoxy-benzene as a
colorless liquid; MS: 250 (M).sup.+.
Example 20
The following compounds were obtained in an analogous manner to
that described in example 11) (d), (e) and example 1) (e), (g)
respectively by alkylation of the
(3S,4R,5R)-3-[(4S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-4-(4-hydroxy-ph
enyl)-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic
acid tert-butyl ester with the aforementioned chlorides, followed
by cleavage of the protecting groups by means of hydrogen chloride
in methanol:
1) By alkylation with
1-(3-chloro-propoxymethyl)-3-fluoro-2-methoxy-benzene and
subsequent cleavage of the isopropylidene and the BOC group,
(R)-3-[(3S,4R,5R)-4-[4-[3-(3-fluoro-2-methoxy-benzyloxy)-propoxy]-phenyl]-
5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-3-yloxy]-propane-1,2-diol
as a colorless oil; MS: 650 (M+H).sup.+ ;
2) by alkylation with
1-(3-chloro-propoxymethyl)-4-fluoro-2-methoxy-benzene and
subsequent cleavage of the isopropylidene and the BOC group,
(R)-3-[(3S,4R,5R)-4-[4-[3-(4-fluoro-2-methoxy-benzyloxy)-propoxy]-phenyl]-
5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-3-yloxy]-propane-1,2-diol
as a colorless oil; MS: 650 (M+H).sup.+ ;
3) by alkylation with
1-(3-chloro-propoxymethyl)-4,5-difluoro-2-methoxy-benzene and
subsequent cleavage of the isopropylidene and the BOC group,
(R)-3-[(3S,4R,5R)-4-[4-[3-(4,5-difluoro-2-methoxy-benzyloxy)-propoxy]-phen
yl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-3-yloxy]-propane-1,2-dio
l as a colorless oil; MS: 668 (M+H).sup.+ ;
4) by alkylation with
1-(3-chloro-propoxymethyl)-3,5-difluoro-2-methoxy-benzene and
subsequent cleavage of the isopropylidene and the BOC group,
(R)-3-[(3S,4R,5R)-4-[4-[3-(3,5-difluoro-2-methoxy-benzyloxy)-propoxy]-phen
yl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-3-yloxy]-propane-1,2-dio
l as a colorless oil; MS: 668 (M+H).sup.+.
Example 21
(R)-1-Methoxy-3-[(3S,4R,5R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-
5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-3-ylmethoxy]-propan-2-ol
In analogy to the procedure described in example 1) (h)-(I),
(R)-3-[(3S,4R,5R)-4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-methoxy
-naphthalen-2-ylmethoxy)-piperidin-3-ylmethoxy]-propane-1,2-diol
was treated with di-tert-butyl-dicarbonate in dioxane/water in the
presence of sodium hydrogencarbonate to yield the
(3S,4R,5R))-3-[(2R)-2,3-dihydroxy-propoxymethyl]-4-[4-[3-(2-methoxy-benzyl
oxy)-propoxy]-phenyl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-car
boxylic acid tert-butyl ester. Subsequent mono-tosylation of the
aforementioned diol by toluene-4-sulfochloride in pyridine led to
the
(3S,4R,5R)-3-[(2S)-2-hydroxy-3-(toluene-4-sulfonyloxy)-propoxymethyl]-4-[4
-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-methoxy-naphthalen-2-ylmeth
oxy)-piperidine-1-carboxylic acid tert-butyl ester which after
treatment with NaOH in DMSO yielded the
(3R,4R,5S)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-3-(4-methoxy-nap
hthalen-2-ylmethoxy)-5-[(2R)-oxiranylmethoxymethyl]-piperidine-1-carboxylic
acid tert-butyl ester. Further reaction of the epoxide with sodium
methylate in a mixture of N,N-dimethylformamide and methanol gave
the
(3S,4R,5R)-3-[(2R)-2-hydroxy-3-methoxy-propoxymethyl]-4-{4-[3-(2-methoxy-b
enzyloxy)-propoxy]-phenyl}-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-
1-carboxylic acid tert-butyl ester which was finally deprotected by
treatment with hydrochloric acid in methanol to yield the
(R)-1-methoxy-3-[(3S,4R,5R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]
-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-3-ylmethoxy]-propan-2-ol
as a colorless foam; MS: 660 (M+H).sup.+.
Example A
Capsules
Composition: 1) Compound of formula I; e.g., is (R)-1-methoxy-3- 50
mg [(3S, 4R, 5R)-4-[4-[3-(2-methoxy-benzyloxy)-
propoxy]-phenyl]-5-(4-methoxy-naphthalen-2-
ylmethoxy)-piperidin-3-yloxy]-propan-2-ol 2) Medium-chain mono-,
diglyceride 950 mg
Production: 2) is liquefied by gentle heating and 1) is dissolved
in 2). The mixture is filled into hard or soft gelatine capsules of
suitable size. The hard gelatine capsules maybe sealed, for example
using the Quali-Seal technique.
Example B
Injection Solution in Form of a Mixed Micelle Solution
Composition Compound of formula I, e.g is (R)-1-methoxy-3- 3.0 mg
[(3S, 4R, 5R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-
phenyl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-
piperidin-3-yloxy]-propan-2-ol Sodium glycocholate 98.5 mg Soya
lecithin 158.2 mg Sodium dihydrogen phosphate 1.8 mg
Disodium-hydrogen phosphate 9.5 mg Water for injection purposes ad
1.0 ml
Production: The compound of formula I, sodium glycocholate and Soya
lecithin are dissolved in the required amount of ethanol (or an
adequate volatile solvent). The solvent is evaporated under reduced
pressure and slight heating. The residue is dissolved in the
buffered aqueous phase. The solution is processed by conventional
procedures.
Example C
Tablets
Composition 1) Compound of formula I, e.g is (R)-1-methoxy-3 200 mg
[(3S, 4R, 5R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-
phenyl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-
piperidin-3-yloxy]-propan-2-ol 2) Anhydrous lactose 160 mg 3)
Hydroxypropylmethylcellulose 18 mg 4) Sodium-carboxymethylcellulose
20 mg 5) Magnesium stearate 2 mg Tablet weight 400 mg
Production: 1) and 2) are mixed intensively. The mixture is
thereafter moistened with an aqueous solution of 3) and kneaded,
and the resulting mass is granulated, dried and sieved. The
granulate is mixed with 4) and 5) and pressed to tablets of
suitable size.
Upon reading the present specification various alternative
embodiments will become obvious to the skilled artisan. These
variations are to be considered within the scope and spirit of the
subject invention, which is only to be limited by the claims that
follow and their equivalents.
* * * * *